Fused heterocyclic compounds

ABSTRACT

The present invention provides a compound of the formula: wherein ring A is an optionally substituted 5 to 10-membered aromatic ring; R 1  and R 2  are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond and the like; and L is a divalent hydrocarbon group, and a salt thereof, except 3-(aminomethyl)-2,6,7-trimethyl-4-phenyl-1(2H)-isoquinolinone, 3-(aminomethyl)-2-methyl-4-phenyl-1(2H)-isoquinolinone, 3-(aminomethyl)-6-chloro-2-methyl-4-phenyl-1(2H)-isoquinolinone and 3-(aminomethyl)-2-isopropyl-4-phenyl-1(2H)-isoquinolinone. The compound shows a superior peptidase-inhibitory activity and is useful as an agent for the prophylaxis or treatment of diabetes and the like.

TECHNICAL FIELD

The present invention relates to a novel fused heterocyclic compoundhaving a peptidase (preferably dipeptidyl dipeptidase IV) inhibitoryactivity, which is useful as a prophylactic or therapeutic agent ofdiabetes and the like.

BACKGROUND ART

Peptidase is known to relate to various diseases. Dipeptidyl dipeptidaseIV (hereinafter sometimes to be abbreviated as DPP-IV), which is onekind of peptidases, is serine protease that specifically binds with apeptide containing proline (or alanine) at the 2nd from the N terminaland cleaves the C-terminal side of the proline (or alanine) to producedipeptide. DPP-IV has been shown to be the same molecule as CD26, andreported to be also involved in the immune system. While the role ofDPP-IV in mammals has not been entirely clarified, it is considered toplay an important role in the metabolism of neuropeptides, activation ofT cells, adhesion of cancerous cells to endothelial cells, invasion ofHIV into cells and the like. Particularly, from the aspect ofglycometabolism, DPP-IV is involved in the inactivation of GLP-1(glucagon-like peptide-1) and GIP (Gastric inhibitorypeptide/Glucose-dependent insulinotropic peptide), which are incretins.With regard to GLP-1, moreover, its half-life in plasma is as short as1–2 minutes, and GLP-1 is known to be degraded by DPP-IV and markedlylose its physiological activity because GLP-1 (9-36)amide, which is adegradation product by DPP-IV, acts on GLP-1 receptor as an antagonist.It is also known that suppression of degradation of GLP-1 by inhibitingactivity of DPP-IV leads to potentiation of physiological activity-thatGLP-1 shows, such as glucose concentration-dependent insulinotropiceffect and the like. From these facts, a compound having a DPP-IVinhibitory activity is expected to show effect on impaired glucosetolerance, postprandial hyperglycemia and fasting hyperglycemia observedin type I and type II diabetes and the like, , obesity or diabeticcomplications associated therewith and the like.

As therapeutic agents of diabetes now in use, a sulfonylurea, abiguanide, an α-glucosidase inhibitor and the like are known. While asulfonylurea produce a potent hypoglycemic action, it sometimes causesserious hypoglycemia and requires attention during use. A biguanideeasily causes lactic acidosis which is a relatively serious side effect.An α-glucosidase inhibitor delays digestion and absorption of glucose inthe gastrointestinal tract and suppresses increase in the blood glucoselevel after meal, but side effects of sense of distension, diarrhea andthe like are problematic (JOSLIN'S DIABETES MELLITUS 13Th Edition521–522).

Isoquinolone compounds are described in the following publications.

-   (1) JP-A-7-76573 describes a compound of the formula

wherein ring A and ring B are optionally substituted benzene rings; Q isan oxygen atom or a sulfur atom; R is a hydrogen atom, an optionallysubstituted hydrocarbon group and the like; W is —CH₂OH, —CH₂NHR¹,—CH₂CH₂NHR¹ (R¹ is hydrogen atom or optionally substituted hydrocarbongroup) and the like, as a starting material compound of a compoundhaving a calcium antagonistic action and the like, wherein the specificexamples are

-   (2) Archiv der Pharmazie, vol. 324, pp. 809–814 (1991) describes a    compound of the formula

-    as a starting material compound of a compound having an    anticonvulsant action.-   (3) JP-A-7-10844 describes a compound of the formula

-    wherein ring A is optionally substituted; ring B is an optionally    substituted benzene ring; one of X and Y is —NR¹— (R¹ is a hydrogen    atom, an optionally substituted hydrocarbon group and the like), —O—    or —S—, the other is —CO—, —CS— and the like;    is a single bond or a double bond; Z is a carbon atom and the like;    D′ is a C₁₋₃ alkylene group; and R⁵ is a hydrogen atom or an    optionally substituted hydrocarbon group] as a starting material    compound of a compound having an acyl-CoA cholesterol acyl    transferase (ACAT) inhibitory action and the like.

However, there is no report showing that these compounds have apeptidase (preferably DPP-IV) inhibitory activity.

There is a demand on the development of a compound having a peptidase(preferably DPP-IV) inhibitory activity, useful as a prophylactic ortherapeutic drug of diabetes and the like and having superior propertiesin terms of efficacy, duration of action, specificity, low toxicity andthe like.

SUMMARY OF THE INVENTION

The present inventors have first found that a compound of the formula

wherein

-   ring A is an optionally substituted 5 to 10-membered aromatic ring;-   R¹ and R² are the same or different and each is an optionally    substituted hydrocarbon group or an optionally substituted    heterocyclic group;-   X is a bond, —O—, —S—, —SO—, —SO₂— or —NR³— (R³ is a hydrogen atom    or an optionally substituted hydrocarbon group); and-   L is a divalent hydrocarbon group,    and a salt thereof,    which are characterized by the chamical structure where an amino    group is bonded to a fused heterocycle via a divalent hydrocarbon    group,    have a superior peptidase (preferably DPP-IV) inhibitory activity    and are useful as a prophylactic or therapeutic agent of diabetes    and the like. Based on this finding, the present inventors have    conducted intensive studies and completed the present invention.

Accordingly, the present invention relates to:

-   1) a compound of the formula (I) or a salt thereof except    3-(aminomethyl)-2,6,7-trimethyl-4-phenyl-1(2H)-isoquinolinone,    3-(aminomethyl)-2-methyl-4-phenyl-1(2H)-isoquinolinone,    3-(aminomethyl)-6-chloro-2-methyl-4-phenyl-1(2H)-isoquinolinone and    3-(aminomethyl)-2-isopropyl-4-phenyl-1(2H)-isoquinolinone,-   2) the compound of 1), wherein the 5 to 10-membered aromatic ring    for ring A is a benzene ring,-   3) the compound of 1), wherein the ring A is a 5 to 10-membered    aromatic ring optionally having 1 to 3 substituent(s) selected from-   a) a halogen atom,-   b) a nitro group,-   c) a cyano group,-   d) a C₁₋₃ alkylenedioxy group,-   e) a C₁₋₁₀ alkyl group or a C₂₋₁₀ alkenyl group, each optionally    having 1 to 3 substituent(s) selected from a halogen atom, a hydroxy    group, a carboxyl group, an alkoxycarbonyl group having 2 to 8    carbon atoms, a carbamoyl group, a cyano group, an amino group, an    alkanoylamino group having 2 to 8 carbon atoms, an    alkoxycarbonylamino group having 2 to 8 carbon atoms, an    alkylsulfonylamino group having 1 to 8 carbon atoms,-   f) an optionally substituted hydroxy group,-   g) an acyl group,-   h) an optionally substituted amino group,-   i) an aryl group having 6 to 14 carbon atoms,-   j) an optionally substituted thiol group, and-   k) an optionally substituted heterocyclic group,-   4) the compound of 1), wherein R¹ is an alkyl group having 1 to 10    carbon atom(s),-   5) the compound of 1), wherein R¹ is an alkyl group having 4 to 10    carbon atoms,-   6) the compound of 1), wherein X is a bond or —O—,-   7) the compound of 1), wherein the divalent hydrocarbon group for L    is an alkylene group having 1 to 10 carbon atom(s),-   8) the compound of 1), wherein R² is an optionally substituted    hydrocarbon group,-   9) the compound of 1), wherein R² is an alkyl group having 1 to 10    carbon atom(s), an aryl group having 6 to 14 carbon atoms or an    aralkyl group having 7 to 13 carbon atoms, each optionally having 1    to 3 substituent(s) selected from halogen atom, hydroxy group, nitro    group, amino group, optionally halogenated alkyl group having 1 to 6    carbon atom(s), alkoxy group, having 1 to 6 carbon atom(s), aromatic    heterocyclic group and cycloalkyl group having 3 to 10 carbon atoms,-   10) the compound of 1), which is    2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carbonitrile,    2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxylic    acid,    2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxamide,    ethyl    2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxylate,    (E)-3-[3-(aminomethyl,)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenamide,    (E)-3-[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenamide,    3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide,    2-[[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isquinolyl]oxy]acetamide,    or a salt thereof,-   11) a crystal of    2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carbonritrile    or a salt thereof,-   12) a crystal of    2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxamide    or a salt thereof,-   13) a crystal of    2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxamide    or a salt thereof,-   14) a crystal of ethyl    2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxylate    or a salt thereof,-   15) a crystal of    (E)-3-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenamide    or a salt thereof,-   16) a crystal of    (E)-3-[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquiniolyl]-2-propenamide    or a salt thereof,-   17) a crystal of    3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide    or a salt thereof,-   18) a crystal of    2-[[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy]acetamide    or a salt thereof,-   19) a pharmaceutical agent containing a compound of the formula (I)    or a salt thereof,-   20) a pharmaceutical agent comprising the pharmaceutical agent    of 19) above in combination with at least one member selected from    an insulin preparation, an insulin sensitizer, an α-glucosidase    inhibitor, a biguanide and an insulin secretagogue,-   21) an agent for prophylaxis or treatment of diabetes, which    contains a compound of the formula (I), a salt thereof or a prodrug    thereof,-   22) an agent for prophylaxis or treatment of diabetic,    complications, which contains a compound of the formula (I), a salt    thereof or a prodrug thereof,-   23) an agent for prophylaxis or treatment of impaired glucose    tolerance, which contains a compound of the formula (I), a salt    thereof or a prodrug thereof,-   24) an agent for prophylaxis or treatment of obesity, which contains    a compound of the formula (I), a salt thereof or a prodrug thereof,-   25) a peptidase inhibitor containing a compound of the formula (I),    a salt thereof or a prodrug thereof,-   26) the inhibitor, of 25) above, wherein the peptidase is dipeptidyl    dipeptidase IV,-   27) a method of prophylaxis or treatment of diabetes in a mammal,    which method comprising administering a compound of the formula (I),    a salt thereof or a prodrug thereof to the mammal,-   28) a method of prophylaxis or treatment of diabetic complications    in a mammal, which method comprising administering a compound of the    formula (I), a salt thereof or a prodrug thereof to the mammal,-   29) a method of prophylaxis or treatment of impaired glucose    tolerance in a mammal, which method comprising administering a    compound of the formula(I), a salt thereof or a prodrug thereof to    the mammal,-   30) a method of prophylaxis or treatment of obesity in a mammal,    which method comprising administering a compound of the formula (I),    a salt thereof or a prodrug thereof to the mammal,-   31) a method of inhibiting peptidase in a mammal, which method    comprising administering a compound of the formula (I), a salt    thereof or a prodrug thereof to the mammal,-   32) use of a compound of the formula (I), a salt thereof or a    prodrug thereof for production of an agent for prophylaxis or    treatment of diabetes,-   33) use of a compound of the formula (I), a salt thereof or a    prodrug thereof for production of an agent for prophylaxis or    treatment of diabetic complications,-   34) use of a compound of the formula (I), a salt thereof or a    prodrug thereof for production of an agent for prophylaxis or    treatment of impaired glucose tolerance,-   35) use of a compound of the formula (I), a salt thereof or a    prodrug thereof for production of an agent for prophylaxis or    treatment of obesity,-   36) use of a compound of the formula (I), a salt thereof or a    prodrug thereof for production of a peptidase inhibitor,-   37) a production method of a compound of the formula

wherein

-   ring A is a 5 to 10-membered aromatic ring;-   R¹ and R² are the same or different and each is an optionally    substituted hydrocarbon group or an optionally substituted    heterocyclic group; and-   X is a bond, —O—, —S—, —SO—, —SO₂— or —NR³— (R³ is a hydrogen atom    or an optionally substituted hydrocarbon group),-   or a salt thereof, which method comprises subjecting a compound of    the formula

-   wherein the symbols are as defined above, or a salt thereof, to    hydrolysis,-   38) a compound of the formula

wherein

-   ring A is a 5 to 10-membered aromatic ring;-   R¹ and R² are the same or different and each is an optionally    substituted hydrocarbon group or an optionally substituted    heterocyclic group;-   X is a bond, —O—, —S—, —SO—, —SO₂— or —NR³— (R³is a hydrogen atom or    an optionally substituted hydrocarbon group; and-   Y is a halogen atom,-   or a salt thereof,-   39) a compound of the formula

wherein

-   ring A is a 5 to 10-membered aromatic ring;-   R¹ and R² are the same or different and each is an optionally    substituted hydrocarbon group or an optionally substituted    heterocyclic group;-   X is a bond, —O—, —S—, —SO—, —SO₂— or, —NR³— (R³ is a hydrogen atom    or an optionally substituted hydrocarbon group); and-   Y is a halogen atom,-   or a salt thereof, and the like.

DETAILED DESCRIPTION OF THE INVENTION

Each symbol of the formula (I) is described in detail in the following.

The “5 to 10-membered aromatic ring” of the “optionally substituted 5 to10-membered aromatic ring” for ring A is, for example, a 5 to10-membered aromatic hydrocarbon ring or a 5 to 10-membered aromaticheterocycle.

Preferable examples of the 5 to 10-membered aromatic hydrocarbon ringinclude benzene, naphthalene and the like.

Preferable examples of the 5 to 10-membered aromatic heterocycle includea 5 to 10-membered aromatic heterocycle containing 1 to 4 heteroatom(s)selected from an oxygen atom, a sulfur atom and a nitrogen atom as aring-constituting atom, besides carbon atoms, such as furan, thiophene,pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole,1,2,3-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,3-triazole, pyridine,pyridazine, pyrimidine, triazine, benzofuran, isobenzofuran,benzo[b]thiophene, indole, isoindole, 1H-indazole, benzimidazole,benzoxazole, 1,2-benzoisoxazole, benzothiazole, 1,2-benzoisothiazole,1H-benzotriazole, quinoline, isoquinoline and the like.

The “5 to 10-membered aromatic ring” is preferably a benzene ring, anaphthalene ring, a thiophene ring, a pyridine ring and the like. Ofthese, a benzene ring is preferable.

The “5 to 10-membered aromatic ring” optionally has 1 to 3substituent(s) at substitutable position(s). Examples of the substituentinclude “halogen atom”, “nitro group”, “cyano group”, “C₁₋₃alkylenedioxy group”, “optionally substituted alkyl group having 1 to 10carbon atom(s)”, “optionally substituted alkenyl group having 2 to 10carbon atoms”, “optionally substituted alkynyl group having 2 to 10carbon atoms”, “optionally substituted cycloalkyl group having 3 to 10carbon atoms”, “optionally substituted cycloalkenyl group having 3 to 10carbon atoms”, “optionally substituted cycloalkadienyl group having 4 to10 carbon atoms”, “optionally substituted aryl group having 6 to 14carbon atoms”, “optionally substituted heterocyclic group”, “acylgroup”, “optionally substituted amino group”, “optionally substitutedhydroxy group”, “optionally substituted thiol group”, “amidino group”and the like.

As the “halogen atom”, for example, fluorine, chlorine, bromine, iodineand the like can be used, with preference given to fluorine, chlorineand bromine.

Examples of the “C₁₋₃ alkylenedioxy group” include methylenedioxy,ethylenedioxy and the like.

As the “alkyl group having 1 to 10 carbon atom(s)” of the “optionallysubstituted alkyl group having 1 to 10 carbon atom(s)”, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl,pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl,heptyl, octyl, nonyl, decyl and the like can be used.

As the “alkenyl group having 2to 10 carbon atoms” of the “optionallysubstituted alkenyl group having 2 to 10 carbon atoms”, for example,ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl,5-hexenyl, 1-heptenyl, 1-octenyl and the like can be used.

As the “alkynyl group having 2 to 10 carbon atoms” of the “optionallysubstituted alkynyl group having 2 to 10 carbon atoms”, for example,ethynyl, 1-propinyl, 2-propinyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentinyl, 2-pentinyl, 3-pentinyl, 4-pentinyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptinyl, 1-octinyl and the like canbe used.

The aforementioned “alkyl group having 1 to 10 carbon atom(s)”, “alkenylgroup having 2 to 10 carbon atoms” and “alkynyl group having 2 to 10carbon atoms” optionally have 1 to 3 substituent(s) at substitutableposition(s).

As these substituents, for example, cycloalkyl group having 3 to 10carbon atoms, aryl group having 6 to 14 carbon atoms (e.g., phenyl,naphthyl and the like), aromatic heterocyclic group (e.g., thienyl,furyl, pyridyl, oxazolyl, thiazolyl, quinolyl and the like),non-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholino,thiomorpholino, piperidino, pyrrolizinyl, piperazinyl and the like),aralkyl group having 7 to 13 carbon atoms, amino group optionally monoor di-substituted by alkyl having 1 to 4 carbon atom(s) or acyl grouphaving 2 to 8 carbon atoms (e.g., alkanoyl group, alkoxycarbonyl groupand the like), alkylsulfonylamino group having 1 to 8 carbon atom(s),amidino group, acyl group having 2 to 8 carbon atoms (e.g., alkanoylgroup, alkoxycarbonyl group and the like), alkylsulfonyl group having 1to 8 carbon atom(s), carbamoyl group optionally mono or di-substitutedby alkyl having 1 to 4 carbon atom(s), sulfamoyl group optionally monoor di-substituted by alkyl having 1 to 4 carbon atom(s), carboxyl group,hydroxy group, alkoxy group having 1 to 6 carbon atom(s) optionallysubstituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine,bromine, iodine and the like), alkenyloxy group having 2 to 5 carbonatoms optionally substituted by 1 to 3 halogen atom(s,) (e.g., fluorine,chlorine, bromine, iodine and the like), cycloalkyloxy group having 3 to7 carbon atoms, aralkyloxy group having 7 to 13 carbon atoms, aryloxygroup having 6 to 14 carbon atoms (e.g., phenyloxy, naphthyloxy and thelike), thiol group, alkylthio group having 1 to 6 carbon atom(s)optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine,chlorine, bromine, iodine and the like), aralkylthio group having 7 to13 carbon atoms, arylthio group having 6 to 14 carbon atoms (e.g.,phenylthio, naphthylthio and the like), sulfo group, cyano, group, azidegroup, nitro group, nitroso group, halogen atom (e.g., fluorine,chlorine, bromine, iodine) and the like can be used.

The “cycloalkyl group having 3 to 10 carbon atoms” of the “optionallysubstituted cycloalkyl group having 3 to 10 carbon atoms” is, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl,bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and the like.

The “cycloalkenyl group having 3 to 10 carbon atoms” of the “optionallysubstituted cycloalkenyl group having 3 to 10 carbon atoms” is, forexample, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl and the like.

The “optionally substituted cycloalkadienyl group having 4 to 10 carbonatoms” of the “optionally substituted cycloalkadienyl group having 4 to10 carbon atoms” is, for example, 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.

The “aryl group having 6 to 14 carbon atoms” of the “optionallysubstituted aryl group having 6 to 14 carbon atoms” is, for example,phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl andthe like. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like arepreferable.

The “heterocyclic group” of the “optionally substituted heterocyclicgroup” is exemplified by non-aromatic heterocyclic group and aromaticheterocyclic group.

The non-aromatic heterocyclic group is, for example, 5 to 7-memberedmonocyclic non-aromatic heterocyclic group or fused non-aromaticheterocyclic group, containing 1 to 4 heteroatom(s) selected from anoxygen atom, a sulfur atom and a nitrogen atom as a ring-constitutingatom, besides carbon atoms. The non-aromatic fused heterocycle group is,for example, a group wherein these 5 to 7-membered monocyclicnon-aromatic heterocyclic groups and a 6-membered ring containing 1 or 2nitrogen atom(s), a benzene ring or a 5-membered ring containing onesulfur atom are fused and the like.

Preferable examples of the non-aromatic heterocyclic group include1-pyrrolizinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl,hexamethylenimin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl,imidazolidin-3-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin-3-yl,2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl,1,3-dioxoisoindol-2-yl, 5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl andthe like.

The aromatic heterocyclic group is, for example, a 5 to 7-memberedmonocyclic aromatic heterocyclic group or fused aromatic heterocyclicgroup, containing 1 to 4 heteroatom(s) selected from an oxygen atom, asulfur atom and a nitrogen atom as a ring-constituting atom, besidescarbon atoms. The fused aromatic heterocyclic group is, for example, agroup where these 5 to 7-membered monocyclic aromatic heterocyclicgroups and a 6-membered ring containing 1 or 2 nitrogen atom(s), abenzene ring or a 5-membered ring, containing one sulfur atom are fusedand the like.

Preferable examples of the aromatic heterocyclic group include 2-furyl,3-furyl, 2-thienyl, -3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,3,4-thiadiazol-2-yl, 1,2,4-triazol-1-yl,-1,2,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,tetrazol-4-yl, tetrazol-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl,2-quinazolyl, 4-quinazolyl, 2-quinoxalyl, 2-benzofuryl, 3-benzofuryl,2-benzothienyl, 3-benzothienyl, 2-benzoxazolyl, 2-benzothiazolyl,benzimidazol-1-yl, benzimidazol-2-yl, indol-1-yl, indol-3-yl,1H-indazol-3-yl, 1H-pyrrolo[2,3-b]pyrazin-2-yl,1H-pyrrolo[2,3-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, 1H-imidazo[4,5-b]pyrazin-2-yl and thelike.

The substituent of the aforementioned “optionally substituted cycloalkylgroup having 3 to 10 carbon atoms”, “optionally substituted cycloalkenylgroup having 3 to 10 carbon atoms”, “optionally substitutedcycloalkadienyl group having 4 to 10 carbon atoms”, “optionallysubstituted aryl group having 6 to 14 carbon atoms” and “optionallysubstituted heterocyclic group” is, for example, alkyl group having 1 to6 carbon atom(s) optionally substituted by 1 to 3 halogen atom(s) (e.g.,fluorine, chlorine, bromine, iodine and the like); alkenyl group having2 to 6 carbon atoms optionally substituted by 1 to 3 halogen atom(s)(e.g., fluorine, chlorine, bromine, iodine and the like); cycloalkylgroup having 3 to 10 carbon atoms; aryl group having 6 to 14 carbonatoms (e.g., phenyl, naphthyl and the like); aromatic heterocyclic group(e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl and the like);non-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholino,thiomorpholino, piperidino, pyrrolizinyl, piperazinyl and the like);aralkyl group having 7 to 13 carbon atoms; amino group optionally monoor di-substituted by alkyl group having 1 to 4 carbon atom(s) or acylgroup having 1 to 15 carbon atom(s) (preferably having 2 to 8 carbonatoms) (e.g., alkanoyl group and the like), such as amino, mono- ordi-C₂₋₁₀ alkanoylamino, C₁₋₁₀ alkoxy-carbonylamino, carbamoylamino,mono- or di-C₁₋₁₀ alkyl-carbamoylamino, C₆₋₁₄ aryl-carbonylamino, C₃₋₁₀cycloalkyl-carbonylamino, C₇₋₁₃ aralkyloxy-carbonylamino, mono- ordi-C₁₋₁₀ alkylsulfonylamino, C₆₋₁₄ arylsulfonylamino, C₁₋₆alkoxy-carbamoylamino and the like; amidino group; acyl group having 2to 8 carbon atoms (e.g., alkanoyl group and the like); carbamoyl groupoptionally mono or di-substituted by alkyl group having 1 to 4 carbonatom(s); sulfamoyl group optionally mono or di-substituted by alkylgroup having 1 to 4 carbon atom(s); carboxyl group; alkoxycarbonyl grouphaving 2 to 8 carbon atoms; hydroxy group; alkoxy group having 1 to 6carbon atom(s) optionally substituted by 1 to 3 halogen atom(s) (e.g.,fluorine, chlorine, bromine, iodine and the like); alkenyloxy grouphaving 2 to 5 carbon atoms optionally substituted by 1 to 3 halogenatom(s) (e.g., fluorine, chlorine, bromine, iodine and the like);cycloalkyloxy group having 3 to 7 carbon atoms; aralkyloxy group having7 to 13 carbon atoms; aryloxy group having 6 to 14 carbon atoms (e.g.,phenyloxy, naphthyloxy and the like); thiol group; alkylthio grouphaving 1 to 6 carbon atom(s) optionally substituted by 1 to 3 halogenatom(s) (e.g., fluorine, chlorine, bromine, iodine and the like);aralkylthio group having 7 to 13 carbon atoms; arylthio group having 6to 14 carbon atoms (e.g., phenylthio, naphthylthio and the like); sulfogroup; cyano group; azide group; nitro group; nitroso group; halogenatom (e.g., fluorine, chlorine, bromine, iodine and the like) and thelike. The number of the substituent is, for example, 1 to 3.

The “acyl group” is, for example, a group of the formula: —COR⁴,—CO—OR⁴, —SO₂R⁴, —SOR⁴, —PO₃R⁴R⁵, —CO—NR^(4a)R^(5a), —CS—NR^(4a)R^(5a)wherein R⁴ and R⁵ are the same or different and each is hydrogen atom,optionally substituted hydrocarbon group or optionally substitutedheterocyclic group. R^(4a) and R^(5a) are the same or different and eachis hydrogen atom, optionally substituted hydrocarbon group or optionallysubstituted heterocyclic group and R^(4a) and R^(5a) may form, togetherwith the adjacent nitrogen atom an optionally substituted,nitrogen-containing heterocycle, and the like.

The “optionally substituted hydrocarbon group” for R⁴, R⁵, R^(4a) andR^(5a) is exemplified by “optionally substituted alkyl group having 1 to10 carbon atom(s)”, “optionally substituted alkenyl group having 2 to 10carbon atoms”, “optionally substituted alkynyl group having 2 to 10carbon atoms”, “optionally substituted cycloalkyl group having 3 to 10carbon atoms”, “optionally substituted cycloalkenyl group having 3 to 10carbon atoms”, “optionally substituted cycloalkadienyl group having 4 to10 carbon atoms”, “optionally substituted aryl group having 6 to 14carbon atoms”, “optionally substituted aralkyl group having 7 to 13carbon atoms”, “optionally substituted arylalkenyl group having 8 to 13carbon atoms” and the like, which are mentioned as the substituents inring A.

The “aralkyl group having 7 to 13 carbon atoms” of the “optionallysubstituted aralkyl group having 7 to 13 carbon atoms” is, for example,benzyl, phenethyl, naphthylmethyl and the like.

The “arylalkenyl group having 8 to 13 carbon atoms” of the “optionallysubstituted arylalkenyl group having 8 to 13 carbon atoms” is, forexample, styryl and the like.

The substituent of the “optionally substituted aralkyl group having 7 to13 carbon atoms” and “optionally substituted arylalkenyl group having 8to 13 carbon atoms” is exemplified by that mentioned as the substituentin the aforementioned “optionally substituted cycloalkyl group having 3to 10 carbon atoms” and the like. The number of the substituent is, forexample, 1 to 3.

The “optionally substituted heterocyclic group” for R⁴, R⁵, R^(4a) orR^(5a) is exemplified by that mentioned as the substituent in ring A.

The “nitrogen-containing heterocycle” of the “optionally substituted,nitrogen-containing heterocycle” formed by R^(4a) and R^(5a) togetherwith the adjacent nitrogen atom is, for example, a 5 to 7-membered,nitrogen-containing heterocycle containing at least one nitrogen atomand further 1 or 2 heteroatom(s) selected from oxygen atom, sulfur atomand nitrogen atom as a ring-constituting atom, besides carbon atoms.Preferable examples of the nitrogen-containing heterocycle includepyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine,morpholine, thiomorpholine and the like.

The nitrogen-containing heterocycle optionally has 1 or 2 substituent(s)at substitutable position(s). Examples of the substituent includehydroxy group, C₁₋₆ alkyl group optionally substituted by 1 to 3 halogenatom(s) (e.g., fluorine, chlorine, bromine, iodine and the like), C₇₋₁₃aralkyl group (e.g., benzyl, diphenylmethyl and the like) and the like.

Preferable examples of the “acyl group” include formyl, carboxyl,carbamoyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl, isobutanoyl, isopentanoyland the like), C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like),C₆₋₁₄ aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl and thelike), C₆₋₁₄ aryloxy-carbonyl (e.g., phenyloxycarbonyl,naphthyloxycarbonyl and the like), C₇₋₁₃ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl and the like), mono- or di-(C₁₋₆alkyl optionally having 1 to 3 substituent(s) selected from halogen atomand C₁₋₆ alkoxy-carbonyl)-carbamoyl (e.g., methylcarbamoylethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl, propylcarbamoyl, trifluoroethylcarbamoyl and thelike), C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl and the like), C₃₋₁₀cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl and the like), C₇₋₁₃aralkyl-carbamoyl (e. g., benzylcarbamoyl and the like), C₁₋₆alkylsulfonyl (e.g., methylsulfonyl and the like), C₆₋₁₄ arylsulfonyl(e.g., phenylsulfonyl and the like), nitrogen-containingheterocycle-carbonyl optionally substituted by hydroxy (e.g.,pyrrolidinylcarbonyl, piperidinocarbonyl and the like), C₁₋₆alkylsulfinyl, (e.g., methylsulfinyl and the like), C₁₋₆alkoxy-carbamoyl (e.g., methoxycarbamoyl), aminocarbamoyl,hydroxycarbamoyl, thiocarbamoyl and the like.

The “optionally substituted amino group” is, for example, amino groupoptionally substituted by 1 or 2 substituent(s) selected from alkylgroup having 1 to 10 carbon atom(s), alkenyl group having 2 to 10 carbonatoms, cycloalkyl group having 3 to 10 carbon atoms, cycloalkenyl grouphaving 3 to 10 carbon atoms, aryl group having 6 to 14 carbon atoms andacyl.

The “alkyl group having 1 to 10 carbon atom(s)”, “alkenyl group having 2to 10 carbon atoms”, “cycloalkyl group having 3 to 10 carbon atoms”,“cycloalkenyl group having 3 to 10 carbon atoms”, “aryl group having 6to 14 carbon atoms” and “acyl group” are exemplified by those mentionedas the substituent in ring A.

Preferable examples of the substituted amino group include mono- ordi-C₁₋₁₀ alkylamino (e.g., methylamino, dimethylamino, ethylamino,diethylamino, propylamino, dibutylamino), mono- or di-C₂₋₁₀ alkenylamino(e.g., diallylamino), mono- or di-C₃₋₁₀ cycloalkylamino (e.g.,cyclohexylamino), mono- or di-C₂₋₁₀ alkanoylamino (e.g., acetylamino,propionylamino, butanoylamino, isobutanoylamino, isopentanoylamino),C₆₋₁₄ aryl-carbonylamino (e.g., benzoylamino), C₆₋₁₄ arylamino (e.g.,phenylamino), carbamoylamino, mono- or di-C₁₋₁₀ alkyl-carbamoylamino(e.g., methylcarbamoylamino, dimethylcarbamoylamino), C₁₋₁₀alkoxy-carbonylamino (e.g., methoxycarbonylamino), C₇₋₁₃aralkyloxy-carbonylamino (e.g., benzyloxycarbonylamino), C₃₋₁₀cycloalkyl-carbonylamino (e.g., cyclopentylcarbonylamino,cyclohexylcarbonylamino), mono- or di-C₁₋₁₀ alkylsulfonylamino (e.g.,methylsulfonylamino, dimethylsulfonylamino), C₆₋₁₄ arylsulfonylamino(e.g., phenylsulfonylamino), C₁₋₆ alkoxy-carbamoylamino (e.g.,methoxycarbamoylamino) and the like.

The “optionally substituted hydroxy group” is, for example, hydroxygroup optionally substituted by “alkyl group having 1 to 10 carbonatom(s)”, “alkenyl group having 2 to 10 carbon atoms”, “alkynyl grouphaving 2 to 10 carbon atoms”, “cycloalkyl group having 3 to 10 carbonatoms”, “cycloalkenyl group having 3 to 10 carbon atoms”, “aryl grouphaving 6 to 14 carbon atoms” or “aralkyl group having 7 to 13 carbonatoms”, each of which is optionally substituted.

The “alkyl having 1 to 10 carbon atom(s)”, “alkenyl group having 2 to 10carbon atoms”, “alkynyl group having 2 to 10 carbon atoms”, “cycloalkylgroup having 3 to 10 carbon atoms”, “cycloalkenyl group having 3 to 10carbon atoms”, “aryl group having 6 to 14 carbon atoms” and “aralkylhaving 7 to 13 carbon atoms” are exemplified by those mentioned as theaforementioned R⁴ and the like.

These “alkyl group having 1 to 10 carbon atom(s)”, “alkenyl group having2 to 10 carbon atoms”, “alkynyl group having 2 to 10 carbon atoms”,“cycloalkyl group having 3 to 10 carbon atoms”, “cycloalkenyl grouphaving 3 to 10 carbon atoms”, “aryl group having 6 to 14 carbon atoms”and “aralkyl group having 7 to 13 carbon atoms” each optionally have 1to 3 substituent(s) at substitutable position(s). Such substituents are,for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine andthe like), alkoxy group having 1 to 3 carbon atom(s), alkoxycarbonylgroup having 2 to 5 carbon atoms, alkanoyl group having 2 to 5 carbonatoms, cyano group, carbamoyl group, hydroxy group, cycloalkyl grouphaving 3 to 10 carbon atoms, carboxyl group, amino group, alkanoylaminogroup having 2 to 5 carbon atoms and the like.

The substituted hydroxy group is preferably “alkoxy group having 1 to 10carbon atom(s)”, “alkenyloxy group having 2 to 10 carbon atoms”,“alkynyloxy group having 2 to 10 carbon atoms”, “cycloalkyloxy grouphaving 3 to 10 carbon atoms”, “cycloalkenyloxy group having 3 to 10carbon atoms”, “aryloxy group having 6 to 14 carbon atoms”, “aralkyloxygroup having 7 to 13 carbon atoms” and the like, each optionally having1 to 3 substituent(s) selected from halogen atom (e.g., fluorine,chlorine, bromine, iodine and the like), alkoxy group having 1 to 3carbon atom(s), alkoxycarbonyl group having 2 to 5 carbon atoms,alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group,hydroxy group, carboxyl group, amino group, alkanoylamino group having 2to 5 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms.

The “alkoxy group having 1 to 10 carbon atom(s)” is, for example,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy,t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy,nonyloxy and the like.

The “alkenyloxy group having 2 to 10 carbon atoms” is, for example,allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like.

The “alkynyloxy group having 2 to 10 carbon atoms” is, for example,ethynyloxy, propinyloxy, pentinyloxy and the like.

The “cycloalkyloxy group having 3 to 10 carbon atoms” is, for example,cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

The “cycloalkenyloxy group having 3 to 10 carbon atoms” is, for example,2-cyclopentenyloxy, 2-cyclohexenyloxy and the like.

The “aryloxy group having 6 to 14 carbon atoms” is, for example,phenoxy, naphthyloxy and the like.

The “aralkyloxy group having 7 to 13 carbon atoms” is, for example,benzyloxy, phenethyloxy, naphthylmethyloxy and the like.

The substituted hydroxy group is more preferably “alkoxy group having 1to 10 carbon atom(s)”, “cycloalkyloxy group having 3 to 10 carbon atoms”or “aralkyloxy group having 7 to 13 carbon atoms”, each optionallyhaving 1 to 3 substituent(s) selected from halogen atom (e.g., fluorine,chlorine, bromine, iodine and the like), alkoxy group having 1 to 3carbon atom(s), alkoxycarbonyl group having 2 to 5 carbon atoms,alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group,hydroxy group, carboxyl group, amino group, alkanoylamino group having 2to 5 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms.

The “optionally substituted thiol group” is, for example, thiol groupoptionally substituted by “alkyl group having 1 to 10 carbon atom(s)”,“alkenyl group having 2 to 10 carbon atoms”, “alkynyl group having 2 to10 carbon atoms”, “cycloalkyl group having 3 to 10 carbon atoms”,“cycloalkenyl group having 3 to 10 carbon atoms”, “aryl group having 6to 14 carbon atoms” or “aralkyl group having 7 to 13 carbon atoms”, eachof which is optionally substituted.

These “alkyl group having 1 to 10 carbon atom(s)”, “alkenyl group having2 to 10 carbon atoms”, “alkynyl group having 2 to 10 carbon atoms”,“cycloalkenyl group having 3 to 10 carbon atoms”, “cycloalkyl grouphaving 3 to 10 carbon atoms”, “aryl group having 6 to 14 carbon atoms”and “aralkyl group having 7 to 13 carbon atoms” are exemplified by thosementioned as the aforementioned R⁴ and the like.

These “alkyl group having 1 to 10 carbon atom(s)”, “alkenyl group having2 to 10 carbon atoms”, “alkynyl group having 2 to 10 carbon atoms”,“cycloalkyl group having 3 to 10 carbon atoms”, “cycloalkenyl grouphaving 3 to 10 carbon atoms”, “aryl group having 6 to 14 carbon atoms”and “aralkyl group having 7 to 13 carbon atoms” each optionally have 1to 3 substituent(s) at substitutable position(s). These substituentsare, for example, halogen atom (e.g., fluorine, chlorine, bromine,iodine and the like), alkoxy group having 1 to 3 carbon atom(s),alkoxycarbonyl group having 2 to 5 carbon atoms, alkanoyl group having 2to 5 carbon atoms, cyano group, carbamoyl group, hydroxy group,cycloalkyl group having 3 to 10 carbon atoms, carboxyl group, aminogroup, alkanoylamino group having 2 to 5 carbon atoms and the like.

The substituted thiol group is preferably “alkylthio group having 1 to10 carbon atom(s)”, “alkenylthio group having 2 to 10 carbon atom”,“alkynylthio group having 2 to 10 carbon atoms”, “cycloatlkylthio grouphaving 3 to 10 carbon atoms”, “cycloalkenylthio group having 3 to 10carbon atoms”, “arylthio group having 6 to 14 carbon atoms”,“aralkylthio group having 7 to 13 carbon atoms” and the like, eachoptionally having 1 to 3 substituent(s) selected from halogen atom(e.g., fluorine, chlorine, bromine, iodine and the like), alkoxy grouphaving 1 to 3 carbon atom(s), alkoxycarbonyl group having 2 to 5 carbonatoms, alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoylgroup, hydroxy group, carboxyl group, amino group, alkanoylamino grouphaving 2 to 5 carbon atoms and cycloalkyl group having 3 to 10 carbonatoms.

The “alkylthio group having 1 to 10 carbon atom(s)” is, for example,methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec.-butylthio, t.-butylthio, pentylthio, isopentylthio,neopentylthio, hexylthio, heptylthio, nonylthio and the like.

The “alkenylthio group having 2 to 10 carbon atoms” is, for example,allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio and the like.

The “alkynylthio group having 2 to 10 carbon atoms” is, for example,ethynylthio, propinylthio, pentinylthio and the like.

The “cycloalkylthio group having 3 to 10 carbon atoms” is, for example,cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.

The “cycloalkenylthio group having 3 to 10 carbon atoms” is, forexample, 2-cyclopentenylthio, 2-cyclohexenylthio and the like.

The “arylthio group having 6 to 14 carbon atoms” is, for example,phenylthio, naphthylthio and the like.

The “aralkylthio having 7 to 13 carbon atoms” is, for example,benzylthio, phenethylthio, naphthylmethylthio and the like.

The substituted thiol group is more preferably alkylthio group having 1to 10 carbon atom(s) optionally substituted by carbamoyl group.

Preferable examples of the “substituent” of “5 to 10-membered aromaticring” for ring A are

-   (1) a halogen atom (e.g., fluorine, chlorine, bromine, iodine and    the like);-   (2) a nitro group;-   (3) a cyano group;-   (4) a C₁₋₃ alkylenedioxy group (e.g., methylenedioxy);-   (5) a C₁₋₁₀ alkyl group (e.g., methyl, ethyl) or a C₂₋₁₀ alkenyl    group (e.g., ethenyl), each optionally having 1 to 3 substituent(s)    selected from halogen atom, hydroxy group, carboxyl group,    alkoxycarbonyl group having 2 to 8 carbon atoms (e.g.,    ethoxycarbonyl), carbamoyl group, cyano group, amino group,    alkanoylamino group having 2 to 8 carbon atoms (e.g., acetylamino,    isobutanoylamino), alkoxycarbonylamino group having 2 to 8 carbon    atoms (e.g., ethoxycarbonylamino) and alkylsulfonylamino group    having 1 to 8 carbon atom(s) (e.g., methylsulfonylamino);-   (6) an optionally substituted hydroxy group [e.g., alkoxy group    having 1 to 10 carbon atom(s) (e.g., methoxy, ethoxy, propoxy,    isopropoxy, butoxy, isobutoxy), cycloalkyloxy group having 3 to 10    carbon atoms (e.g., cyclopentyloxy) or aralkyloxy group having 7 to    13 carbon atoms (e.g., benzyloxy), each optionally having 1 to 3    substituent(s) selected from halogen atom, alkoxy group having 1 to    3 carbon atom(s) (e.g., methoxy), alkoxycarbonyl group having 2 to 5    carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl), alkanoyl group    having 2 to 5 carbon atoms (e.g., pivaloyl), cyano group, carbamoyl    group, hydroxy group, carboxyl group, amino group, alkanoylamino    group having 2 to 5 carbon atoms (e.g., acetylamino) and cycloalkyl    group having 3 to 10 carbon atoms (e.g., cyclopropyl, cyclohexyl);    hydroxy group];-   (7) an acyl group [e.g., formyl, carboxyl, C₁₋₆ alkyl-carbonyl    (e.g., acetyl), C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl),    carbamoyl, aminocarbamoyl, hydroxycarbamoyl, mono- or di-(C₁₋₆ alkyl    optionally having 1 to 3 substituent(s) selected from halogen atom    and C₁₋₆ alkoxy-carbonyl (e.g., ethoxycarbonyl))-carbamoyl (e.g.,    methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl,    trifluoroethylcarbamoyl, ethoxycarbonylmethylcarbamoyl and the    like), C₃₋₁₀ cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),    C₇₋₁₃ aralkyl-carbamoyl (e.g., benzylcarbamoyl), nitrogen-containing    heterocycle-carbonyl optionally substituted by hydroxy. (e.g.,    pyrrolidinylcarbonyl, piperidinocarbonyl), C₁₋₆ alkylsulfonyl (e.g.,    methylsulfonyl), C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl),    thiocarbamoyl];-   (8) an optionally substituted amino group [e.g., amino, mono- or    di-C₂₋₁₀ alkanoylamino (e.g., acetylamino, propionylamino,    isobutanoylamino, isopentanoylamino), C₁₋₁₀ alkoxy-carbonylamino    (e.g., methoxycarbonylamino), carbamoylamino, mono- or di-C₁₋₁₀    alkyl-carbamoylamino (e.g., methylcarbamoylamino,    dimethylcarbamoylamino), C₆₋₁₄ aryl-carbonylamino (e.g.,    benzoylamino), C₃₋₁₀ cycloalkyl-carbonylamino (e.g.,    cyclopentylcarbonylamino), C₇₋₁₃ aralkyloxy-carbonylamino (e.g.,    benzyloxycarbonylamino), mono- or di-C₁₋₁₀ alkylsulfonylamino (e.g.,    methylsulfonylamino, dimethylsulfonylamino), C₆₋₁₄ arylsulfonylamino    (e.g., phenylsulfonylamino), C₁₋₆ alkoxy-carbamoylamino (e.g.,    methoxycarbamoylamino)];-   (9) an aryl group having 6 to 14 carbon atoms (e.g., phenyl);-   (10) an optionally substituted thiol group [e.g., alkylthio group    having 1 to 10 carbon atom(s) optionally substituted by carbamoyl    group (e.g., methylthio)];-   (11) an optionally substituted heterocyclic group [e.g., aromatic    heterocyclic group (preferably furyl, thienyl, oxazolyl,    oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or    non-aromatic heterocyclic group (preferably dioxoisoindole,    5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl), each optionally having 1    or 2 substituent(s) selected from C₁₋₆, alkyl group optionally    substituted by 1 to 3 halogen atom(s) (e.g., methyl,    trifluoromethyl), carboxyl group, alkoxycarbonyl group having 2 to 8    carbon atoms (preferably ethoxycarbonyl), cyano group, carbamoyl    group, amino group, mono- or di-C₂₋₁₀ alkanoylamino group (e.g.,    acetylamino, isopentanoylamino), C₁₋₁₀ alkoxy-carbonylamino group    (e.g., methoxycarbonylamino), carbamoylamino group, mono- or    di-C₁₋₁₀ alkyl-carbamoylamino group (e.g., methylcarbamoylamino,    dimethylcarbamoylamino), C₆₋₁₄ aryl-carbonylamino group (e.g.,    benzoylamino), C₃₋₁₀ cycloalkyl-carbonylamino group, C₇₋₁₃    aralkyloxy-carbonylamino group, mono- or di-C₁₋₁₀ alkylsulfonylamino    group (e.g., methylsulfonylamino, dimethylsulfonylamino), C₆₋₁₄    arylsulfonylamino group and C₁₋₆ alkoxy-carbamoylamino group (e.g.,    methoxycarbamoylamino)];-   (12) an amidino group;    and the like.

The number of substituent is preferably 1 to 3, more preferably 1 or 2.

The “substituent” of the “5 to 10-membered aromatic ring” for ring A ispreferably

-   (1) a halogen atom (e.g., fluorine, chlorine, bromine, iodine and    the like);-   (2) a nitro group;-   (3) a cyano group;-   (4) a C₁₋₃alkylenedioxy group (e.g., methylenedioxy);-   (5) a C₁₋₁₀ alkyl group or a C₂₋₁₀ alkenyl group, each optionally    having 1 to 3 substituent(s) selected from halogen atom, hydroxy    group, carboxyl group, alkoxycarbonyl group having 2 to 8 carbon    atoms, carbamoyl group, cyano group, amino group, alkanoylamino    group having 2 to 8 carbon atoms, alkoxycarbonylamino group having 2    to 8 carbon atoms, alkylsulfonylamino group having 1 to 8 carbon    atoms;-   (6) an optionally substituted hydroxy group (e.g., alkoxy group    having 1 to 10 carbon atom(s), cycloalkyloxy group having 3 to 10    carbon atoms or aralkyloxy group having 7 to 13 carbon atoms each    optionally having 1 to 3 substituent(s) selected from halogen atom,    alkoxy group having 1 to 3 carbon atom(s), alkoxycarbonyl group    having 2 to 5 carbon atoms, alkanoyl group having 2 to 5 carbon    atoms, cyano group, carbamoyl group, hydroxy group, carboxyl group    and cycloalkyl group having 3 to 10 carbon atoms; hydroxy group);-   (7) an acyl group (e.g., carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl,    mono- or di-(C₁₋₆ alkyl optionally having 1 to 3 substituent(s)    selected from halogen atom and C₁₋₆ alkoxy-carbonyl)-carbamoyl,    C₃₋₁₀ cycloalkyl-carbamoyl, C₇₋₁₃ aralkyl-carbamoyl,    nitrogen-containing heterocycle-carbonyl optionally substituted by    hydroxy, C₁₋₆ alkyl-carbonyl, thiocarbamoyl, C₁₋₆ alkylsulfonyl,    C₁₋₆ alkylsulfinyl);-   (8) an optionally substituted amino group (e.g., amino, mono- or    di-C₂₋₁₀ alkanoylamino, C₁₋₁₀ alkoxy-carbonylamino, mono- or    di-C₁₋₁₀ alkyl-carbamoylamino, C₆₋₁₄ aryl-carbonylamino, C₃₋₁₀    cycloalkyl-carbonylamino, C₇₋₁₃ aralkyloxy-carbonylamino, mono- or    di-C₁₋₁₀ alkylsulfonylamino, C₆₋₁₄ arylsulfonylamino,    carbamoylamino); or-   (9) an optionally substituted heterocyclic group [e.g., aromatic    heterocyclic group (preferably furyl, thienyl, oxazolyl,    oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or    non-aromatic heterocyclic group (preferably dioxoisoindole,    5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl)], each optionally having    1 or 2 substituent(s) selected from C₁₋₆ alkyl group optionally    substituted by 1 to 3 halogen atom(s), carboxyl group,    alkoxycarbonyl group having 2 to 8 carbon atoms, cyano group,    carbamoyl group, amino group, mono- or di-C₂₋₁₀ alkanoylamino group,    C₁₋₁₀ alkoxy-carbonylamino group, carbamoylamino group, mono-    or-di-C₁₋₁₀ alkyl-carbamoylamino group, C₆₋₁₄ aryl-carbonylamino    group, C₃₋₁₀ cycloalkyl-carbonylamino,group, C₇₋₁₃    aralkyloxy-carbonylamino group, mono- or di-C₁₋₁₀ alkylsulfonylamino    group, C₆₋₁₄ arylsulfonylamino group and C₁₋₆ alkoxy-carbamoylamino    group.

The number of substituent is preferably 1 to 3, more preferably 1 or 2.

The “substituent” of the “5 to 10-membered aromatic ring” for ring A ismore preferably

-   (1) a halogen atom (e.g., fluorine, chlorine, bromine, iodine and    the like);-   (2) a nitro group;-   (3) a cyano group;-   (4) a C₁₋₃ alkylenedioxy group (e.g., methylenedioxy);-   (5) an optionally substituted hydroxy group (preferably methoxy,    carbamoylmethoxy and the like);-   (6) an acyl group (preferably carbamoyl, methoxycarbonyl and the    like);-   (7) an optionally substituted amino group (preferably acetylamino    and the like);-   (8) a C₁₋₁₀ alkyl group (preferably ethyl) or a C₂₋₁₀ alkenyl group    (preferably ethenyl), each optionally substituted by carbamoyl    group;-   (9) an optionally substituted heterocyclic group [e.g., aromatic    heterocyclic group (preferably furyl, thienyl, oxazolyl,    oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or    non-aromatic heterocyclic group (preferably dioxoisoindole,    5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl), each optionally having 1    or 2 substituent(s) selected from C₁₋₆ alkyl group optionally    substituted by 1 to 3 halogen atom(s), carboxyl group,    alkoxycarbonyl group having 2 to 8 carbon atoms, cyano group,    carbamoyl group, amino group, mono- or di-C₂₋₁₀ alkanoylamino group,    C₁₋₁₀ alkoxy-carbonylamino group, carbamoylamino group, mono- or    di-C₁₋₁₀ alkyl-carbamoylamino group, C₆₋₁₄ aryl-carbonylamino group,    C₃₋₁₀ cycloalkyl-carbonylamino group, C₇₋₁₃ aralkyloxy-carbonylamino    group, mono- or di-C₁₋₁₀ alkylsulfonylamino group, C₆₋₁₄    arylsulfonylamino group and C₁₋₆ alkoxy-carbamoylamino group]. The    number of substituent is preferably 1 or 2.

The ring A is preferably benzene ring optionally having 1 or 2substituent(s) selected from

-   (1) a cyano group;-   (2) a C₁₋₁₀ alkyl group (preferably ethyl) or a C₂₋₁₀ alkenyl group    (preferably ethenyl), each optionally having 1 to 3 substituent(s)    selected from carbamoyl group, carboxyl group and alkoxycarbonyl    group having 2 to 8 carbon atoms (preferably methoxycarbonyl);-   (3) an optionally substituted hydroxy group [preferably alkoxy group    having 1 to 10 carbon atom(s) (preferably methoxy, isopropoxy)    optionally having 1 to 3 substituent(s) selected from carbamoyl    group, carboxyl group and alkoxycarbonyl group having 2 to 5 carbon    atoms (preferably methoxycarbonyl); hydroxy group; aralkyloxy group    having 7 to 13 carbon atoms (preferably benzyloxy)] [more preferably    carbamoylmethoxy];-   (4) an acyl group [preferably C₁₋₆ alkyl-carbonyl (preferably    acetyl), carbamoyl, mono- or di-(C₁₋₆ alkyl optionally having 1 to 3    substituent(s) selected from halogen atom and C₁₋₆    alkoxy-carbonyl)-carbamoyl (preferably methylcarbamoyl,    ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl,    trifluoroethylcarbamoyl, ethoxycarbonylmethylcarbamoyl and the    like), C₃₋₁₀ cycloalkyl-carbamoyl (preferably cyclopropylcarbamoyl),    C₇₋₁₃ aralkyl-carbamoyl (preferably benzylcarbamoyl),    nitrogen-containing heterocycle-carbonyl optionally substituted by    hydroxy (preferably pyrrolidinylcarbonyl, piperidinocarbonyl), C₁₋₆    alkylsulfonyl (preferably methylsulfonyl), C₁₋₆ alkylsulfinyl    (preferably methylsulfinyl), carboxyl, C₁₋₆ alkoxy-carbonyl    (preferably methoxycarbonyl), thiocarbamoyl];-   (5) an optionally substituted amino group (preferably    carbamoylamino);-   (6) an optionally substituted thiol group [preferably alkylthio    group having 1 to 10 carbon atom(s) optionally substituted by    carbamoyl group (preferably methylthio)];-   (7) an optionally substituted heterocyclic group [preferably    aromatic heterocyclic group (preferably furyl, thienyl, oxazolyl,    oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or    non-aromatic heterocyclic group (preferably dioxoisoindole,    5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl), each optionally having 1    or 2 substituent(s) selected from C₁₋₆ alkyl group optionally    substituted by 1 to 3 halogen atom(s) (preferably methyl,    trifluoromethyl), carboxyl group, alkoxycarbonyl group having 2 to 8    carbon atoms (preferably ethoxycarbonyl), cyano group, carbamoyl    group, amino group, mono- or di-C₂₋₁₀ alkanoylamino group (e.g.,    acetylamino, isopentanoylamino), C₁₋₁₀ alkoxy-carbonylamino group    (e.g., methoxycarbonylamino), carbamoylamino group, mono- or    di-C₁₋₁₀ alkyl-carbamoylamino group (e.g., methylcarbamoylamino,    dimethylcarbamoylamino), C₆₋₁₄ aryl-carbonylamino group (e.g.,    benzoylamino), C₃₋₁₀ cycloalkyl-carbonylamino group, C₇₋₁₃    aralkyloxy-carbonylamino group, mono- or di-C₁₋₁₀ alkylsulfonylamino    group (e.g., methylsulfonylamino, dimethylsulfonylamino), C₆₋₁₄    arylsulfonylamino group and C₁₋₆ alkoxy, carbamoylamino group (e.g.,    methoxycarbamoylamino)]; and-   (8) an amidino group.

The ring A is more preferably a benzene ring having 1 or 2substituent(s) selected from

-   (1) a C₁₋₁₀ alkyl group (preferably ethyl) or a C₂₋₁₀ alkenyl group    (preferably ethenyl), each having 1 to 3 substituent(s) selected    from carbamoyl group, carboxyl group and alkoxycarbonyl group having    2 to 8 carbon atoms (preferably methoxycarbonyl);-   (2) an optionally substituted hydroxy group [preferably alkoxy group    having 1 to 10 carbon atom(s) (preferably methoxy, isopropoxy)    optionally having 1 to 3 substituent(s) selected from carbamoyl    group, carboxyl group and alkoxycarbonyl group having 2 to 5 carbon    atoms (preferably methoxycarbonyl); hydroxy group; aralkyloxy group    having 7 to 13 carbon atom(s) (preferably benzyloxy)] [more    preferably carbamoylmethoxy];-   (3) an acyl group [preferably C₁₋₆ alkyl-carbonyl (preferably    acetyl), carbamoyl, mono- or di-(C₁₋₆ alkyl optionally having 1 to 3    substituent(s) selected from halogen atom and C₁₋₆    alkoxy-carbonyl)-carbamoyl (preferably methylcarbamoyl,    ethylcarbamoyl propylcarbamoyl, dimethylcarbamoyl,    trifluoroethylcarbamoyl ethoxycarbonylmethylcarbamoyl and the like),    C₃₋₁₀ cycloalkyl-carbamoyl (preferably cyclopropylcarbamoyl), C₇₋₁₃    aralkyl-carbamoyl (preferably benzylcarbamoyl), nitrogen-containing    heterocycle-carbonyl optionally substituted by hydroxy (preferably    pyrrolidinylcarbonyl, piperidinocarbonyl), C₁₋₆ alkylsulfonyl    (preferably methylsulfonyl), C₁₋₆ alkylsulfinyl (preferably    methylsulfinyl), carboxyl, C₁₋₆ alkoxy-carbonyl (preferably    methoxycarbonyl), thiocarbamoyl]; and-   (4) an optionally substituted heterocyclic group [preferably    aromatic heterocyclic group (preferably furyl, thienyl, oxazolyl,    oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or    non-aromatic heterocyclic group (preferably dioxoisoindole,    5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl), each optionally having 1    or 2 substituent(s), selected from C₁₋₆ alkyl optionally substituted    by 1 to 3 halogen atom(s) (preferably methyl, trifluoromethyl),    carboxyl group alkoxycarbonyl group, having 2 to 8 carbon atoms    (preferably ethoxycarbonyl), cyano group, carbamoyl group, amino,    mono- or di-C₂₋₁₀ alkanoylamino (e.g., acetylamino,    isopentanoylamino), C₁₋₁₀ alkoxy-carbonylamino (.e.g.,    methoxycarbonylamino), carbamoylamino, mono- or di-C₁₋₁₀    alkyl-carbamoylamino (e.g., methylcarbamoylamino,    dimethylcarbamoylamino), C₆₋₁₄ aryl-carbonylamino (e.g.,    benzoylamino), C₃₋₁₀ cycloalkyl-carbonylamino, C₇₋₁₃    aralkyloxy-carbonylamino, mono- or di-C₁₋₁₀ alkylsulfonylamino    (e.g., methylsulfonylamino, dimethylsulfonylamino), C₆₋₁₄    arylsulfonylamino, and C₁₋₆ alkoxy-carbamoylamino (e.g.,    methoxycarbamoylamino)].

Examples of the “optionally substituted hydrocarbon group” for R¹ and R²are those exemplified for the aforementioned R⁴ and the like.

Examples of the “optionally substituted heterocyclic group” for R¹ andR² are those exemplified as the substituent in ring A.

R¹ is preferably an optionally substituted hydrocarbon and morepreferably an alkyl group having 1 to 10 carbon atom(s) which isoptionally substituted by cycloalkyl group having 3 to 10 carbon atoms(e.g., cyclopropyl and the like). R¹ is particularly preferably an alkylgroup having 4 to 10 carbon atoms or a cycloalkylalkyl group having 4 to10 carbon atoms (preferably cyclopropylmethyl). Of these, preferred isan alkyl group having 4 or 5 carbon atoms (e.g., butyl, isobutyl,sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl andthe like).

R²is preferably an optionally substituted hydrocarbon group. Morepreferably, R² is an alkyl group having 1 to 10 substituent(s) (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl,pentyl and the like), aryl group having 6 to 14 carbon atoms (e.g.,phenyl and the like) or aralkyl group having 7 to 13 carbon atoms (e.g.,benzyl, phenethyl, naphthylmethyl and the like), each optionally having1 to 3 (preferably 1 or 2) substituent(s) selected from halogen atom(e.g., fluorine, chlorine and the like), hydroxy group, nitro group,amino group, optionally halogenated alkyl group having 1 to 6carbonatom(s) (e.g., trifluoromethyl, methyl and the like), alkoxy grouphaving 1 to 6 carbon atom(s) (e.g., methoxy and the like), aromaticheterocyclic group (e.g., quinolyl, thienyl and the like) and cycloalkylgroup having 3 to 10 carbon atoms (e.g., cyclopentyl and the like).

X is a bond, —O—, —S—, —SO—, —SO₂— or —NR³— (R³ is hydrogen atom oroptionally substituted hydrocarbon group).

Examples of the “optionally substituted hydrocarbon group” for R³ arethose exemplified for the aforementioned R⁴ and the like. The“optionally substituted hydrocarbon group” is preferably alkyl grouphaving 1 to 10 carbon atom(s) (e.g., methyl, ethyl and the like) and thelike.

In the formula (I), when X is a bond, R² is preferably an aryl grouphaving 6 to 14 carbon atoms (e.g., phenyl and the like) optionallyhaving 1 or 2 substituent(s) selected from halogen atom (e.g., fluorine,chlorine and the like), hydroxy group, nitro group, amino group,optionally halogenated alkyl group having 1 to 6 carbon atom(s) (e.g.,trifluoromethyl, methyl and the like), alkoxy group having 1 to 6 carbonatom(s) (e.g., methoxy and the like), aromatic heterocyclic group (e.g.,quinolyl, thienyl and the like) and cycloalkyl group having 3 to 10carbon atoms (e.g., cyclopentyl and the like).

In the formula (I), when X is —O—, —S—, —SO—, —SO₂— or —NR³—, R² ispreferably an alkyl group having 1 to 10 carbon atom(s) (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyland the like) or an aralkyl group having 7 to 13 carbon atoms (e.g.,benzyl and the like), each optionally having 1 to 3 (preferably 1 or 2)substituent(s) selected from halogen atom (e.g., fluorine and the like),hydroxy group, nitro group, optionally halogenated alkyl group having 1to 6 carbon atom(s) (e.g., trifluoromethyl and the like), alkoxy grouphaving 1 to 6 carbon atom(s) (e.g., methoxy and the like), aromaticheterocyclic group (e.g., quinolyl, thienyl and the like) and cycloalkylgroup having 3 to 10 substituents (e.g., cyclopentyl and the like).

X is preferably a bond or —O—.

The “divalent hydrocarbon group” for L is, for example,

-   (1) C₁₋₁₀ alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,    —(CH₂)₅—, —(CH₂)₆—, —CHCH₃—, —C(CH₃)₂—, —(CH(CH₃))₂—,    —(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂— and the like);-   (2) C₂₋₁₀ alkenylene (e.g., —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—,    —CH═CH—CH₂—CH₂—, —C(CH₃)₂—CH═CH—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—,    —CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— and the like); or-   (3) C₂₋₁₀ alkynylene (e.g., —C≡C—, —CH₂—C≡C—, —C₂—C≡C—CH₂—CH₂— and    the like) and the like.

The “divalent hydrocarbon group” is preferably C₁₋₁₀ alkylene, morepreferably, —CH₂—, —(CH₂)₂— and the like. Particularly, —CH₂— ispreferable.

Preferable examples of compound (I) include the following compounds.

[Compound A]

A compound wherein ring A is a benzene ring, a naphthalene ring or athiophene ring, each optionally having 1 or 2 substituent(s) selectedfrom

-   (1) a halogen atom;-   (2) a nitro group;-   (3) a cyano group;-   (4) a C₁₋₃ alkylenedioxy group;-   (5) an optionally substituted hydroxy group (preferably methoxy,    carbamoylmethoxy and the like);-   (6) an acyl group (preferably carbamoyl, methoxycarbonyl and the    like); and-   (7) an optionally substituted amino group (preferably acetylamino    and the like);-   R¹ is an alkyl group having 1 to 10 carbon atom(s) (preferably alkyl    group having 4 to 10 carbon atom(s));-   R² is an alkyl group having 1 to 10 carbon atom(s), an aryl group    having 6 to 14 carbon atoms or an aralkyl group having 7 to 13    carbon atoms, each optionally having 1 or 2 substituent(s) selected    from halogen atom, hydroxy group, nitro group, optionally    halogenated alkyl group having 1 to 6 carbon atom(s), alkoxy groups    having 1 to 6 carbon atom(s) aromatic heterocyclic group (e.g.    quinolyl and the like) and cycloalkyl group having 3 to 10 carbon    atoms;-   X is a bond or —O—; and-   L is C₁₋₁₀ alkylene.    [Compound B]

A compound wherein ring A is a benzene ring optionally having 1 or 2substituent(s) selected from

-   (1) a cyano group;-   (2) a C₁₋₁₀ alkyl group (preferably ethyl) or a C₂₋₁₀ alkenyl group    (preferably ethenyl), each optionally substituted by carbamoyl group    or carboxyl group;-   (3) an optionally substituted hydroxy group [preferably alkoxy group    having 1 to 10 carbon atom((s) (preferably methoxy, isopropoxy)    optionally having 1 to 3 substituent(s) selected from carbamoyl    group, carboxyl group and alkoxycarbonyl group having 2 to 5 carbon    atoms (preferably methoxycarbonyl); hydroxy group; aralkyloxy group    having 7 to 13 carbon atoms (preferably benzyloxy)] [more preferably    carbamoylmethoxy];-   (4) an acyl group [preferably C₁₋₆ alkyl-carbonyl (preferably    acetyl), carbamoyl, mono- or di-(C₁₋₆ alkyl optionally having 1 to 3    substituent(s) selected from halogen atom and C₁₋₆    alkoxy-carbonyl)-carbamoyl (preferably methylcarbamoyl,    ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl,    trifluoroethylcarbamoyl, ethoxycarbonylmethylcarbamoyl and the    like), C₃₋₁₀ cycloalkyl-carbamoyl (preferably cyclopropylcarbamoyl),    C₇₋₁₃ aralkyl-carbamoyl (preferably benzylcarbamoyl),    nitrogen-containing heterocycle-carbonyl optionally substituted by    hydroxy (preferably pyrrolidinylcarbonyl, piperidinocarbonyl), C₁₋₆    alkylsulfonyl (preferably methylsulfonyl), C₁₋₆ alkylsulfinyl    (preferably methylsulfinyl), carboxyl, C₁₋₆ alkoxy-carbonyl    (preferably methoxycarbonyl), thiocarbamoyl];-   (5) an optionally substituted amino group (preferably    carbamoylamino);-   (6) an optionally substituted thiol group [preferably alkylthio    group having 1 to 10 carbon atom(s) optionally substituted by    carbamoyl group (preferably methylthio);-   (7) an optionally substituted heterocyclic group [preferably    aromatic heterocyclic group (preferably furyl, thienyl, oxazolyl,    oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or    non-aromatic heterocyclic group (preferably dioxoisoindole,    5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl), each optionally having 1    or 2 substituent(s) selected from C₁₋₆ alkyl group optionally    substituted by 1 to 3 halogen atom(s) (preferably methyl,    trifluoromethyl), carboxyl group, alkoxycarbonyl group having 2to 8    carbon atoms (preferably ethoxycarbonyl), cyano group, carbamoyl    group, amino group, mono- or di-C₂₋₁₀ alkanoylamino group (e.g.,    acetylamino, isopentanoylamino), C₁₋₁₀ alkoxy-carbonylamino group    (e.g., methoxycarbonylamino), carbamoylamino group, mono- or    di-C₁₋₁₀ alkyl-carbamoylamino group (e.g., methylcarbamoylamino,    dimethylcarbamoylamino), C₆₋₁₄ aryl-carbonylamino group (e.g.,    benzoylamino), C₃₋₁₀ cycloalkyl-carbonylamino group, C₇₋₁₃    aralkyloxy-carbonylamino group, mono- or di-C₁₋₁₀ alkylsulfonylamino    group (e.g., methylsulfonylamino, dimethylsulfonylamino), C₆₋₁₄    arylsulfonylamino group and C₁₋₆ alkoxy-carbamoylamino group (e.g.,    methoxycarbamoylamino); and-   (8) an amidino group;-   R¹ is an alkyl group having 4 to 10 carbon atoms (preferably    isobutyl, neopentyl) or a cycloalkylalkyl group having 4 to 10    carbon atoms (preferably cyclopropylmethyl);-   R² is an aryl group having 6 to 14 carbon atoms (preferably phenyl)    optionally having 1 or 2 substituent(s) selected from halogen atom    (preferably fluorine, chlorine) and C₁₋₆ alkyl (preferably methyl);-   X is a bond; and-   L is C₁₋₁₀ alkylene (preferably —CH₂—).    [Compound C]

A compound wherein ring A is is a benzene ring optionally having 1 or 2substituent(s) selected from

-   (1) a C₁₋₁₀ alkyl group (preferably ethyl) or a C₂₋₁₀ alkenyl group    (preferably ethenyl), each optionally substituted by alkoxycarbonyl    group having 2 to 8 carbon atoms (preferably ethoxycarbonyl) or    carbamoyl group;-   (2) an optionally substituted hydroxy group [preferably alkoxy group    having 1 to 10 carbon atom(s) (preferably methoxy) optionally    substituted by carbamoyl group; more preferably carbamoylmethoxy];-   (3) an acyl group (preferably carbamoyl, thiocarbamoyl, carboxyl);-   (4) an optionally substituted heterocyclic group [preferably    aromatic heterocyclic group (preferably furyl, thienyl, oxazolyl,    oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or    non-aromatic heterocyclic group (preferably 5-oxooxadiazol-3-yl),    each optionally having 1 or 2 substituent(s) selected from C₁₋₆    alkyl group (preferably methyl), carboxyl group, alkoxycarbonyl    group having 2 to 8 carbon atoms (preferably ethoxycarbonyl), cyano    group, carbamoyl group, amino group, mono- or di-C₂₋₁₀ alkanoylamino    group (e.g., acetylamino, isopentanoylamino), C₁₋₁₀    alkoxy-carbonylamino group (e.g., methoxycarbonylamino),    carbamoylamino group, mono- or di-C₁₋₁₀ alkyl-carbamoylamino group    (e.g., methylcarbamoylamino, dimethylcarbamoylamino), C₆₋₁₄    aryl-carbonylamino group (e.g., benzoylamino), C₃₋₁₀    cycloalkyl-carbonylamino group, C₇₋₁₃ aralkyloxy-carbonylamino    group, mono- or di-C₁₋₁₀ alkylsulfonylamino group (e.g.,    methylsulfonylamino, dimethylsulfonylamino), C₆₋₁₄ arylsulfonylamino    group and, C₁₋₆ alkoxy-carbamoylamino group (e.g.,    methoxycarbamoylamino)];-   R¹ is an alkyl group having 4 to 10 carbon atoms (preferably    isobutyl, neopentyl) or a cycloalkylalkyl group having 4 to 10    carbon atom(s) (preferably cyclopropylmethyl);-   R² is an alkyl group having 1 to 10 carbon atom(s), which is    optionally substituted by 1 to 3 halogen atom(s) (preferably butyl);-   X is —O—; and-   L is C₁₋₁₀ alkylene (preferably —CH₂—).

Preferable examples of compound (I) include compounds shown by thefollowing formula.

TABLE 1 No. X R¹ R² R⁶ R⁷ R⁸ R⁹ 1 O neo-Pent n-Bu H EtO— H H 2 Oneo-Pent n-Bu H H F H 3 O neo-Pent n-Bu H F H H 4 O Me Me H Cl H H 5 OMe Me H H Cl H 6 O Me i-Pr H Cl H H 7 O Me n-Bu H Cl H H 8 O Me PhCH₂— HCl H H 9 O Me a) H Cl H H 10 O Me PhCH₂CH₂— H Cl H H 11 O Me b) H Cl H H12 — Me Ph H H Cl H 13 O Me n-Pr H Cl H H 14 O Me c) H Cl H H 15 O Me4-NO₂Ph H Cl H H 16 — Me 4-MeOph H Cl H H 17 — Me 3-MeOPh H Cl H H 18 —Me 4-HOPh H Cl H H 19 — Me 3-HOPh H Cl H H 20 — Me 4-FPh H Cl H H 21 —Me 4-F₃CPh H Cl H H 22 — Me Ph H Cl Cl H 23 — Me 3-NO₂Ph H Cl H H 24 —Me 3-NH₂Ph H Cl H H 25 O n-Pr n-Bu H Cl H H

TABLE 2 No. X R¹ R² R⁶ R⁷ R⁸ R⁹ 26 O i-Bu n-Bu H Cl Cl H 27 O neo-Pentn-Bu H Cl Cl H 28 O PhCH₂— n-Bu H Cl Cl H 29 O i-Bu n-Pent H Cl Cl H 30O i-Pr n-Bu H Cl Cl H 31 O c-Pr n-Bu H Cl Cl H 32 O c-PrCH₂— n-Bu H ClCl H 33 O i-Pent n-Bu H Cl Cl H 34 O neo-Pent i-Bu H Cl Cl H 35 O d)n-Bu H Cl Cl H 36 O Me n-Bu H Cl Cl H 41 O e) n-Bu H Cl Cl H 42 O f)n-Bu H Cl Cl H 43 O g) n-Bu H Cl Cl H 44 O h) n-Bu H Cl Cl H 45 O i)n-Bu H Cl Cl H 46 O neo-Pent n-Bu H H H H 47 O j) n-Bu H Cl Cl H 48 OMeOCH₂CH₂— n-Bu H Cl Cl H 49 O neo-Pent MeOCH₂CH₂— H H H H 50 O neo-Pentn-Bu H H Me H

TABLE 3 No. X R¹ R² R⁶ R⁷ R⁸ R⁹ 51 O neo-Pent n-Bu H Me H H 52 Oneo-Pent n-Bu H H CF₃ H 53 O neo-Pent n-Bu H CF₃ H H 54 O k) n-Bu H ClCl H 55 O l) n-Bu H Cl Cl H 57 O neo-Pent n-Bu H MeO— H H 58 O neo-Pentn-Bu H PhCH₂O— H H 59 O neo-Pent n-Bu H HO— H H 60 O neo-Pent n-Bu Hn-PrO— H H 61 O neo-Pent n-Bu H n-BuO— H H 62 O neo-Pent n-Bu HMeOCH₂CH₂O— H H 63 O neo-Pent n-Bu H H PhCH₂O H 64 O neo-Pent n-Bu H HHO— H 65 O neo-Pent n-Bu H H MeO— H 66 O neo-Pent n-Bu H H EtO— H 67 Oneo-Pent n-Bu H H n-PrO H 68 O neo-Pent n-Bu H H n-BuO H 69 O neo-Pentn-Bu MeO MeO— H H 70 O neo-Pent n-Bu H MeO— MeO— H 74 O i-Bu n-Bu H Br HH 75 O i-Bu n-Bu H MeOCO— H H

TABLE 4 No. X R¹ R² R⁶ R⁷ R⁸ R⁹ 76 O i-Bu n-Bu H HOCO— H H 77 O i-Bun-Bu H H₂NCO— H H 78 O i-Bu n-Bu H NC— H H 79 O i-Bu n-Bu H HOCH₂— H H80 O i-Bu n-Bu H MeNHCONH— H H 81 O i-Bu n-Bu H MeOCONH— H H 82 O i-Bun-Bu H NH₂— H H 83 O neo-Pent n-Bu H Br H H 84 O neo-Pent n-Bu H MeOCO—H H 85 O neo-Pent n-Bu H HOCO— H H 86 O neo-Pent n-Bu H H₂NCO— H H 87 Oneo-Pent n-Bu H NC— H H 88 O i-Bu n-Bu H AcNH— H H 89 O i-Bu n-Bu HEtCONH— H H 90 O i-Bu n-Bu H m) H H 91 O i-Bu n-Bu H n) H H 92 O i-Bun-Bu H o) H H 93 O i-Bu n-Bu H MsNH— H H 94 O i-Bu n-Bu H PhSO₂NH— H H95 O nea-Pent n-Bu H p) H H 96 O neo-Pent n-Bu H i-PrO— H H 97 Oneo-Pent n-Bu H CF₃CH₂O— H H 98 O neo-Pent n-Bu H q) H H 99 O neo-Pentn-Bu H r) H H 100 O neo-Pent n-Bu H i-BuO— H H

TABLE 5 No. X R¹ R² R⁶ R⁷ R⁸ R⁹ 101 O neo-Pent n-Bu H s) H H 102 Oneo-Pent n-Bu H t) H H 103 O neo-Pent n-Bu H u) H H 104 O neo-Pent n-BuH EtOCOCH₂O— H H 105 O neo-Pent n-Bu H v) H H 106 — i-Bu Ph H Br H H 107— i-Bu Ph H MeOCO— H H 108 — i-Bu Ph H HOCO— H H 109 — i-Bu Ph H H₂NCO—H H 110 — i-Bu Ph H CbzNH— H H 111 — i-Bu Ph H NH₂— H H 112 — i-Bu Ph HAcNH— H H 113 — Et Ph H Cl H H 114 — n-Pr Ph H Cl H H 115 — n-Bu Ph H ClH H 116 — Me Ph H Br H H 117 — n-Pent Ph H Cl H H 118 — i-Bu Ph H Cl H H119 — c-HexCH₂— Ph H Cl H H 120 — i-Bu 4-FPh H Cl Cl H 121 — i-Bu Ph HCl Cl H 122 — neo-Pent Ph H Cl H H 123 — i-Bu Ph H H H H 124 — i-Bu4-ClPh H H H H 125 — i-Bu 4-MePh H H H H

TABLE 6 No. X R¹ R² R⁶ R⁷ R⁸ R⁹ 126 — i-Bu Ph H F H H 127 — i-Bu Ph HMeO— H H 128 — i-Bu Ph H EtO— H H 129 — i-Bu Ph H n-PrO— H H 130 — i-BuPh H MeO— MeO— H 131 — i-Bu 4-FPh H MeOCO— H H 132 — i-Bu 4-FPh H HOCO—H H 133 — i-Bu 4-FPh H H₂NCO— H H 134 — i-Bu 4-FPh H AcNH— H H 135 —i-Bu 4-FPh H EtO— H H 136 — i-Bu 4-FPh H p) H H 137 — i-Bu 2-FPh HMeOCO— H H 138 — i-Bu 2-FPh H HOCO— H H 139 — i-Bu 2-FPh H H₂NCO— H H140 — i-Bu 2-FPh H AcNH— H H 141 — i-Bu 2-FPh H p) H H 142 — i-Bu 3-FPhH MeOCO— H H 143 — i-Bu 3-FPh H HOCO— H H 144 — i-Bu 3-FPh H H₂NCO— H H145 — i-Bu 3-FPh H AcNH— H H 146 — i-Bu 3-FPh H EtO— H H 147 — i-Bu Ph HMeNHCONH— H H 148 — i-Bu Ph H Me₂NCONH— H H 149 — i-Bu Ph H H₂NCONH— H H150 O i-Bu CF₃CH₂CH₂CH₂— H p) H H

TABLE 7 No. X R¹ R² R⁶ R⁷ R⁸ R⁹ 151 O c-PrCH₂— n-Bu H H₂NCO— H H 152 Oc-PrCH₂— n-Bu H p) H H 153 O c-PrCH₂— n-Bu H w) H H 154 O i-Bu n-Bu H p)H H 155 O i-Bu n-Bu H w) H H 156 — i-Bu Ph H NC— H H 157 — i-Bu Ph HMeNHCO— H H 158 — i-Bu Ph H p) H H 159 — i-Bu Ph H w) H H 160 O neo-Pentn-Bu H w) H H 161 O c-PrCH₂— n-Bu H x) H H 162 O i-Bu n-Bu H x) H H 163— i-Bu Ph H x) H H 164 O i-Bu n-Bu H y) H H 165 — i-Bu Ph H y) H H 166 Oi-Bu n-Bu H z) H H 167 — i-Bu Ph H z) H H 168 O i-Bu n-Bu H aa) H H 169— i-Bu Ph H aa) H H 170 O i-Bu n-Bu H ab) H H 171 — i-Bu Ph H ab) H H172 — i-Bu 4-MePh H p) H H 173 — i-Bu 4-ClPh H p) H H 174 — i-Bu 4-MePhH z) H H 175 — i-Bu 4-ClPh H z) H H 176 — i-Bu 4-MePh H ac) H H

The symbols in the Tables mean the following:

Me: methyl, Et: ethyl, CF₃: trifluoromethyl, neo-Pent: neopentyl, n-Bu:n-butyl, i-Bu: isobutyl, i-Pr: isopropyl, Ph: phenyl, n-Pr: n-propyl,4-NO₂Ph: 4-nitrophenyl, 4-MeOPh: 4-methoxyphenyl, 4-MePh:4-methylphenyl, 4-HOPh: 4-hydroxyphenyl, 3-MeOPh: 3-methoxyphenyl,3-HOPh: 3-hydroxyphenyl, 4-FPh: 4-fluorophenyl, 4-CF₃Ph:4-trifluoromethylphenyl, 3-NO₂Ph: 3-nitrophenyl, 3-NH₂Ph: 3-aminophenyl,n-Pent: n-pentyl, i-Pent: isopentyl, c-Pr: cyclopropyl, c-Hex:cyclohexyl, 4-ClPh: 4-chlorophenyl, 2-FPh: 2-fluorophenyl, 3-FPh:3-fluorophenyl, Cbz: benzyloxycarbonyl, Ac: acetyl, Ms: methanesulfonyl

More Preferable examples of compound (I) include:

-   2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carbonitrile;-   2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxylic    acid;-   2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxamide;-   ethyl    2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxylate;-   (E)-3-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenamide;-   (E)-3-[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenamide;-   3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide;-   2-[[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy]acetamide;    and the like.

As a salt of the compound of the formula (I) (hereinafter sometimes tobe abbreviated as compound (I)), pharamacologically acceptable salt ispreferable. Examples of such salt include salt with inorganic base, saltwith organic base, salt with inorganic acid, salt with organic acid,salt with basic or acidic amino acid and the like.

Preferable examples of the salt with inorganic base include alkali metalsalts such as sodium salt, potassium salt and the like; alkaline earthmetal salts such as calcium salt, magnesium salt and the like; aluminumsalt; ammonium salt and the like.

Preferable examples of the salt with organic base include a salt withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine or the like.

Preferable examples of the salt with inorganic acid include a salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid or the like.

Preferable examples of the salt with organic acid include a salt withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidor the like.

Preferable examples of the salt with basic amino acid include a saltwith arginine, lysin, ornithine or the like.

Preferable examples of the salt with acidic amino acid include a saltwith aspartic acid, glutamic acid or the like.

Of the above-mentioned salts, sodium salt, potassium salt, hydrochlorideand the like are preferable.

A prodrug of compound (I) is a compound that converts to compound (I)due to the reaction of enzyme, gastric acid and the like under thephysiological conditions in the body. That is, a compound that convertsto compound (I) by enzymatic oxidation, reduction, hydrolysis and thelike, and a compound that converts to compound (I) by hydrolysis and thelike by gastric acid and the like. A prodrug of compound (I) isexemplified by a compound wherein an amino group of compound (I) isacylated, alkylated, phosphorylated (e.g., compound where amino group ofcompound (I) is eicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,tert-butylated and the like); compound wherein a hydroxy group ofcompound (I) is acylated, alkylated, phosphorinated, borated (e.g.,compound where hydroxy group of, compound (I) is acetylated,palmitoylated, propanoylated, pivaloylated, succinilated, fumarinated,alanilated, dimethylaminomethylcarbonylated and the like); compoundwherein a carboxyl group of compound (I) is esterified or amidated(e.g., compound where carboxyl group of compound (I) is ethylesterified, phenyl esterified, carboxymethyl esterified,dimethylaminomethyl esterified, pivaloyloxymethyl esterified,ethoxycarbonyloxyethyl esterified, phthalidyl esterified,(5-methyl-2-oxo-1,3dioxolen-4-yl)methyl esterified,cyclohexyloxycarbonyethyl esterified, methylamidated and the like) andthe like. These compounds can be produced from compound (I) by a methodknown per se.

A prodrug of compound (I) may be a compound that converts to compound(I) under physiological conditions as described in Development ofpharmaceutical products, vol. 7, Molecule Design, 163–198, HirokawaShoten (1990).

The compound (I) may be labeled with isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵Iand the like) and the like.

The compound (I) may be an anhydride or a hydrate.

The compound (I), a salt thereof and a prodrug thereof (hereinaftersometimes to be simply referred to as the compound of the presentinvention) show low toxicity and can be used as an agent for theprophylaxis or treatment of various diseases to be mentioned later formammal (e.g., human, mouse, rat, rabbit, dog, cat, cattle, horse, swine,simian and the like) by admixing with a pharmacologically acceptablecarrier and the like to give a pharmaceutical composition.

Here, various organic or inorganic carriers conventionally used asmaterials for pharmaceutical preparations are used as apharmacologically acceptable carrier, which are added as excipient,lubricant, binder, disintegrant for solid preparations; and solvent,dissolution aids, suspending agent, isotonicity agent, buffer, soothingagent and the like for liquid preparations. Where necessary, additivefor pharmaceutical preparations such as preservative, antioxidant,coloring agent, sweetening agent and the like can be used.

Preferable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, pregelatinized starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose, sodiumcarboxymethylcellulose, gum arabic, dextrin, pullulan, light silicicanhydride, synthetic aluminumsilicate, magnesium aluminate metasilicateand the like.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc, colloidal silica and the like.

Preferable examples of the binder include pregelatinized starch,saccharose, gelatin, gum arabic, methylcellulose,carboxymethylcellulose, sodium carboxymethylcellulose, crystallinecellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan,hydroxypropyl cellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone and the like.

Preferable examples of the disintegrant include lactose, sucrose,starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodiumcrosscarmellose, sodium carboxymethyl starch, light silicic anhydride,low-substituted hydroxypropylcellulose and the like.

Preferable examples of the solvent include water for injection,physiological brine, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil andthe like.

Preferable examples of the dissolution aids include polyethylene glycol,propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, Trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, sodium salicylate, sodium acetate and the like.

Preferable examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, monostearicglyceride and the like; hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcelluloseand the like; polysorbates, polyoxyethylene hydrogenated castor oil andthe like.

Preferable examples of the isotonicity agent include sodium chloride,glycerol, D-mannitol, D-sorbitol, glucose and the like.

Preferable examples of the buffer include phosphate buffer, acetatebuffer, carbonate buffer, citrate buffer, and the like.

Preferable examples of the soothing agent include benzyl alcohol and thelike.

Preferable examples of the preservative include p-oxybenzoic acidesters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroaceticacid, sorbic acid and the like.

Preferable examples of the antioxidant include sulfite, ascorbate andthe like.

Preferable examples of the coloring agent include water-soluble edibletar pigment (.e.g., foodcolors such as Food Color Red Nos. 2 and 3, FoodColor Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like,water insoluble lake pigment (e.g., aluminum salt of the aforementionedwater-soluble edible tar pigment and the like), natural pigments (e.g.,beta carotene, chlorophil, red iron oxide etc.) and the like.

Preferable examples of the sweetening agent include saccharin sodium,dipotassium glycyrrhizinate, aspartame, stevia and the like.

The dosage form of the aforementioned pharmaceutical composition may be,for example, oral agents such as tablets (inclusive of sublingualtablets and orally disintegrable tablets), capsules (inclusive of softcapsules and micro capsules), granules, powders, troches, syrups,emulsions, suspensions and the like; or parenteral agents such asinjections (e.g., subcutaneous injections, intravenous injections,intramuscular injections, intraperitoneal injections, drip infusions andthe like), external agents (e.g., transdermal preparations, ointmentsand the like), suppositories (e.g., rectal suppositories, vaginalsuppositories and the like), pellets, nasal preparations, pulmonarypreparations (inhalations), ophthalmic preparations and the like. Thesemay be administered safely via oral or parenteral route. These agentsmay be controlled-release preparations such as rapid-releasepreparations and sustained-release preparations (e.g., sustained-releasemicrocapsules).

The pharmaceutical composition can be produced according to a methodconventionally used in the field of pharmaceutical preparation, such asthe method described in Japan Pharmacopoeia and the like. The specificproduction methods of the pharmaceutical preparation are described indetail in the following.

While the content of the compound of the present invention in thepharmaceutical composition varies depending on dosage form, dose of thecompound of the present invention and the like, it is, for example,about 0.1–100 wt %.

For example, an oral agent is produced by adding, to the activeingredient, excipient (e.g., lactose, sucrose, starch, D-mannitol andthe like), disintegrant (e.g., calcium carboxymethylcellulose and thelike), binder (e.g., pregelatinated starch, gum arabic,carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone andthe like), lubricant (e.g., talc, magnesium stearate, polyethyleneglycol 6000 and the like) and the like, compression-shaping the mixture,and where necessary, coating the same using a coating base for maskingof taste, enteric property or sustained release according to a methodknown per se.

Examples of the coating base include a sugar-coating base, awater-soluble film coating base, an enteric film coating base, asustained release film coating base and the like.

As a sugar-coating base, sucrose may be used, along with one or twospecies selected from talc, precipitated calcium carbonate, gelatin, gumarabic, pullulan, carnauba wax and the like.

As a water-soluble film coating, base, for example, cellulose polymerssuch as hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, methylhydroxyethylcellulose and the like;synthetic polymers such as polyvinyl acetal diethylaminoacetate,aminoalkyl methacrylate copolymer E [Eudragit E, trademark, RohmPharma], polyvinylpyrrolidone and the like; polysaccharides such aspullulan and the like; and the like are used.

As a enteric film coating base, for example, cellulose polymers such ashydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, carboxymethylethylcellulose, acetic phthaliccellulose and the like; acrylic acid polymers, such as methacrylic acidcopolymer L [Eudragit L, trademark, Rohm Pharma], methacrylic acidcopolymer LD [Eudragit L-30D55, trademark, Rohm Pharma], methacrylicacid copolymer S [Eudragit S, trademark, Rohm Pharma] and the like;naturally occurring substance such as shellac and the like; and the likeare used.

As a sustained release film coating base, for example, cellulosepolymers such as ethylcellulose and the like; acrylic acid polymers suchas aminoalkyl methacrylate copolymer RS [Eudragit RS, trademark, RohmPharma], ethyl acrylate methyl methacrylate copolymer suspension[Eudragit NE, trademark, Rohm Pharma] and the like, and the like areused.

Two or more kinds of the above-mentioned coating bases may be mixed inan appropriate ratio for use. In addition, a light shielding agent suchas titanium oxide, iron tri or dioxide and the like may be used duringcoating.

An injection is produced by dissolving, suspending or emulsifying anactive ingredient in an aqueous solvent (e.g., distilled water,physiological saline, Ringer's solution and the like) or an oily solvent(e.g., plant oil such as olive oil, sesame oil, cottonseed oil, corn oiland the like, propylene glycol and the like) and the like, together witha dipersing agent (eg., polysorbate 80, polyoxyethylene hydrogenatedcastor oil 60 and the like), polyethylene glycol,carboxymethylcellulose, sodium alginate and the like), preservative(e.g., methylparaben, propylparaben, benzyl alcohol, chlorobutanol,phenol and the like), isotonicity agent (e.g., sodium chloride,glycerol, D-mannitol, D-sorbitol, glucose and the like) and the like. Inthis step, dissolution aids (e.g., sodium salicylate, sodium acetate andthe like), stabilizers (e.g., human serum albumin and the like),soothing agents (e.g., benzyl alcohol and the like) and the like may beused on demand.

The compound of the present invention and the pharmaceutical agent ofthe present invention show low toxicity, cause fewer side effects andcan be used as an agent for the prophylaxis or treatment or diagnosis ofvarious diseases to be mentioned later for mammal (e.g., human, cattle,horse, dog, cat, simian, mouse, rat, especially human).

The compound of the present invention and the pharmaceutical agent ofthe present invention have a superior peptidase inhibitory activity andcan suppress peptidase-caused degradation of a physiologically activesubstance such as peptide hormones, cytokines, neurotransmitters and thelike.

Examples of the peptide hormones include glucagon-like peptide-1(GLP-1), glucagon-like peptide-2 (GLP-2), GIP, growth hormone releasehormone (GHRH) and the like.

Examples of the cytokines include chemokine such as RANTES and the like.

Examples of the neurotransmitters include neuropeptide Y and the like.

Examples of the peptidase include EC 3.4.11.1 (Leucyl aminopeptidase),EC 3.4.11.2 (Membrane alanine aminopeptidase), EC 3.4.11.3 (Cystinylaminopeptidase), EC 3.4.11.4 (Tripeptide aminopeptidase), EC 3.4.11.5(Prolyl aminopeptidase), EC 3.4.11.6 (Aminopeptidase B), EC 3.4.11.7(Glutamyl aminopeptidase), EC 3.4.11.9 (Xaa-Pro aminopeptidase), EC3.4.11.10 (Bacterial leucyl aminopeptidase), EC 3.4.11.13 (Clostridialaminopeptidase), EC 3.4.11.14 (Cytosol alanyl aminopeptidase), EC3.4.11.15 (Lysyl aminopeptidase), EC 3.4.11.16 (Xaa-Trp aminopeptidase),EC 3.4.11.17 (Tryptophanyl aminopeptidase), EC 3.4.11.18 (Methionylaminopeptidase), EC 3.4.11.19 (D-stereospecific aminopeptidase), EC3.4.11.20 (Aminopeptidase Ey), EC 3.4.11.21 (Aspartyl aminopeptidase),EC 3.4.11.22 (Aminopeptidase I), EC 3.4.13.3 (Xaa-His dipeptidase), EC3.4.13.4 (Xaa-Arg dipeptidase), EC 3.4.13.5 (Xaa-methyl-Hisdipeptidase), EC 3.4.13.7 (Glu-Glu dipeptidase), EC 3.4.13.9 (Xaa-Prodipeptidase), EC 3.4.13.12 (Met-Xaa dipeptidase), EC 3.4.13.17(Non-stereospecific dipeptidase), EC 3.4.13.18 (Cytsol nonspecificdipeptidase), EC 3.4.13.19 (Membrane dipeptidase), EC 3.4.13.20(Beta-Ala-His dipeptidase), EC 3.4.14.1 (Dipeptidyl-peptidase I), EC3.4.14.2 (Dipeptidyl-peptidase II), EC 3.4.14.4 (Dipeptidyl-peptidaseIII), EC 3.4.14.5 (Dipeptidyl-peptidase IV), EC 3.4.14.6(Dipeptidyl-dipeptidase), EC 3.4.14.9 (Tripeptidyl-peptidase I), EC3.4.14.10 (Tripeptidyl-peptidase II) and EC 3.4.14.11 (Xaa-Prodipeptidyl-peptidase) as classified by International Union ofBiochemistry and Molecular Biology (IUBMB), and the like.

Of these, EC 3.4.14.1, EC 3.4.14.2, EC 3.4.14.4, EC 3.4.14.5, EC3.4.14.6, EC 3.4.14.9, EC 3.4.14.10 and EC 3.4.14.11 are preferable.Especially preferred is EC 3.4.14.5.

The compound of the present invention and the pharmaceutical agent ofthe present invention are useful as a prophylactic and therapeutic agentof diabetes (e.g., type 1 diabetes, type 2 diabetes, gestationaldiabetes and the like); prophylactic and therapeutic agent ofhyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, lowHDL lipemia, postprandial lipemia and the like); prophylactic andtherapeutic agent of arteriosclerosis; prophylactic and therapeuticagent of impaired glucose tolerance [IGT]; an insulin secretagogue; andan agent for suppressing progress of impaired glucose tolerance intodiabetes.

For diagnostic criteria of diabetes, Japan Diabetes Society reported newdiagnostic criteria in 1999.

According to this report, diabetes is a condition showing any of afasting blood glucose level (glucose concentration of intravenousplasma) of not less than 126 mg/dl, a 75 g oral glucose tolerance test(75 g OGTT) 2 h level (glucose concentration of intravenous plasma) ofnot less than 200 mg/dl, a non-fasting blood glucose level (glucoseconcentration of intravenous plasma) of not less than 200 mg/dl. Acondition not falling under the above-mentioned diabetes, or “acondition showing a fasting blood glucose level (glucose concentrationof intravenous plasma) of less than 110 mg/dl or a 75 g oral glucosetolerance test (75 g OGTT) 2 h level (glucose concentration ofintravenous plasma) of less than 140 mg/dl” (normal type) is called a“borderline type”.

In addition, ADA (American Diabetes Academy) reported new diagnosticcriteria of diabetes in 1997 and WHO in 1998.

According to these reports, diabetes is a condition showing a fastingblood glucose level (glucose concentration of intravenous plasma) of notless than 126 mg/dl and a 75 g oral glucose tolerance test 2 h level(glucose concentration of intravenous plasma) of not less than 200mg/dl.

According to the above-mentioned reports, impaired glucose tolerance isa condition showing a fasting blood glucose level (glucose concentrationof intravenous plasma) of less than 126 mg/dl and a 75 g oral glucosetolerance test 2 h level (glucose concentration of intravenous plasma)of not less than 140 mg/dl and less than 200 mg/dl. According to thereport of ADA, a condition showing a fasting blood glucose level(glucose concentration of intravenous plasma) of not less than 110 mg/dland less than 126 mg/dl is called IFG (Impaired Fasting Glucose).According to the report of WHO, among the IFG, (Impaired FastingGlucose), a condition showing a 75 g oral glucose tolerance test 2 hlevel (glucose concentration of intravenous plasma) of less than 140mg/dl is called IFG (Impaired Fasting Glycemia).

The compound of the present invention and the pharmaceutical agent ofthe present invention can be also used as a prophylactic and therapeuticagent of diabetes, borderline type, impaired glucose tolerance, IFG(Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia), asdetermined according to the above-mentioned new diagnostic criteria.Moreover, the compound of the present invention and the pharmaceuticalagent of the present invention can prevent progress of borderline type,impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG(Impaired Fasting Glycemia) into diabetes.

The compound of the present invention and the pharmaceutical agent ofthe present invention can be also used as a prophylactic and therapeuticagent of, for example, diabetic complications [e.g., neuropathy,nephropathy, retinopathy, cataract, macroangiopathy, osteopenia,hyperosmolar diabetic coma, infectious disease (respiratory infection,urinary tract infection, gastrointestinal infection, dermal soft tissueinfections, inferior limb infection and the like), diabetic gangrene,xerostomia, hypacusis, cerebrovascular disorder, peripheral bloodcirculation disorder and the like], obesity, osteoporosis, cachexia(e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia,blood disease cachexia, endocrine disease cachexia, infectious diseasecachexia or cachexia due to acquired immunodeficiency syndrome), fattyliver, hypertension, polycystic ovary syndrome, kidney disease (e.g.,diabetic nephropathy, glomerular nephritis, glomerulosclerosis,nephrotic syndrome, hypertensive nephrosclerosis, end stage kidneydisease and the like), muscular dystrophy, myocardial infarction, anginapectoris, cerebrovascular accident (e.g., cerebral infarction, cerebralapoplexy), insulin resistance syndrome, Syndrome X, hyperinsulinemia,hyperinsulinemia-induced sensory disorder, tumor (e.g., leukemia, breastcancer, prostatic cancer, skin cancer and the like), irritable bowelsyndrome, acute or chronic diarrhea, inflammatory diseases (e.g.,chronic rheumatoid arthritis, spondylitis deformans, arthritiscleformans, lumbar pain, gout, postoperative or traumatic inflammation,remission of tumentia, neuralgia, pharyngolaryngitis, cystitis,hepatitis (inclusive of nonalcoholic steatohepatitis), pneumonia,pancreatitis, inflammatory bowel disease, ulcerative colitis, gastricmucosal injury (inclusive of gastric mucosal injury caused by aspirin)and the like), visceral obesity syndrome and the like.

The compound of the present invention and the pharmaceutical agent ofthe present invention can be also used for decreasing visceral, fat,suppressing visceral fat accumulation, improving glycometabolism,improving lipid metabolism, suppressing production of oxidized LDL,improving lipoprotein metabolism, improving coronary artery metabolism,prophylaxis and treatment of cardiovascular complication, prophylaxisand treatment of heart failure complication, lowering blood remnant,prophylaxis and treatment of anovulation, prophylaxis and treatment ofhypertrichosis, prophylaxis and treatment of hyperandrogenemia,improving pancreatic (β cell) function, regeneration of pancreatic (βcell), promotion of pancreatic (β cell) regeneration, and the like.

The compound of the present invention and the pharmaceutical agent ofthe present invention can be also used for secondary prophylaxis andsuppression of progression of the above-mentioned various diseases(e.g., cardiovascular event such as myocardial infarction and the like).

The compound of the present invention and the pharmaceutical agent ofthe present invention is a glucose dependent insulin secretagogue thatselectively promotes insulin secretion in hyperglycemic patients (e.g.,patients showing fasting blood glucose level of not less than 126 mg/dlor 75 g oral glucose tolerance test (75 g OGTT) 2 h level of not lessthan 140 mg/dl and the like). Therefore, the compound of the presentinvention and the pharmaceutical agent of the present invention areuseful as a safe prophylactic or therapeutic agent of diabetes with alow risk of vascular complications, hypoglycemia induction and the likecaused by insulin.

While the dose of the compound of the present invention and thepharmaceutical agent of the present invention varies depending on theadministration subject, administration route, target disease, conditionand the like, the compound of the present invention as an activeingredient is generally given in a single dose of about 0.01–100 mg/kgbody weight, preferably 0.05–30 mg/kg body weight, more preferably0.1–10 mg/kg body weight, in the case of, for example, oraladministration to adult diabetic patients. This dose is desirably given1 to 3 times a day.

The compound of the present invention can be used in combination withtherapeutic agents such as a therapeutic agent of diabetes, atherapeutic agent of diabetic complications, an antihyperlipemia agent,an antihypertensive agent, an antiobestic agent, a diuretic, achemotherapeutic agent, an immunotherapeutic agent, an antithromboticagent, a therapeutic agent of osteoporosis, an antidementia agent, anagent for the improvement of erectile dysfunction, a therapeutic agentof incontinentia or pollakiuria and the like (hereinafter to be referredto as a combination drug). In this case, the timing of administration ofthe compound of the present invention and a combination drug is notlimited. These may be simultaneously administered to an administrationobject or administered in a staggered manner. Moreover, the compound ofthe present invention and a combination drug may be administered as twokinds of preparations each containing an active ingredient, or may beadministered as a single preparation containing both active ingredients.

The dose of the combination drug can be determined as appropriate basedon the dose clinically employed. The proportion of the compound of thepresent invention and combination drug can be appropriately determineddepending on the administration subject, administration route, targetdisease, condition, combination and the like. When, for example, theadministration subject is human, a combination drug is used in an amountof 0.01–100 parts by weight per 1 part by weight of the compound of thepresent invention.

Examples of the therapeutic agent of diabetes include insulinpreparations (e.g., animal insulin preparations extracted from pancreasof cattle, swine; human insulin preparations synthesized by geneticengineering techniques using Escherichia coli or yeast; zinc insulin;protamine zinc insulin; fragments or derivatives of insulin (e.g., INS-1and the like) and the like), insulin sensitizers (e.g., pioglitazonehydrochloride, rosiglitazone (maleate), GI-262570, JTT-501, MCC-555,YM-440, KRP-297, CS-011, FK-614, NN-622, AZ-242, BMS-298585, EML-16336,compounds described in WO99/58510 (e.g.,(E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid) and the like), PPARγ agonists, PPARγ antagonists, PPARγ/α dualagonists, α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol,emiglitate and the like), biguanides (e.g., phenformin, metformin,buformin and the like), insulin secretagogues [sulfonylureas (e.g.,tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide,acetohexamide, gyclopyramide, glimepiride, glipizide, glybuzole and thelike), repaglinide, senaglinide, nateglinide, mitiglinide or calciumsalt hydrate thereof], GLP-1 receptor agonists [e.g., GLP-1, NN-2211,AC-2993 (exendin-4), BIM-51077, Aib(8,35)hGLP-1(7,37)NH₂ and the like],amyrin agonists (e.g., pramlintide and the like), phosphotyrosinephosphatase inhibitors (e.g., vanadic acid and the like),dipeptidylpeptidase IV inhibitors (e.g., NVP-DPP-278, PT-100, P32/98,LAF-237 and the like), β3 agonists (e.g., CL-316243, SR-58611-A,UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 and the like),gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors,glucose-6-phosphatase inhibitors, glucagon antagonists, somatostatinreceptor agonists and the like), SGLT (sodium-glucosecotransporter);inhibitors (e.g., T-1095 and the like) and the like.

Examples of the therapeutic agent of diabetic complications includealdose reductase inhibitors (e.g., Tolrestat, Epalrestat, Zenarestat,Zopolrestat, Minalrestat, Fidarestat, SNK-860, CT-112 and the like),neurotrophic factors and increasing drugs thereof (e.g., NGF, NT-3,BDNF, neurotrophin production secretion promoters described inWO01/14372 (e.g.,4-(4-chlorophenyl)-2-(2methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazoleand the like) and the like), neuranagenesis stimulators (e.g., Y-128 andthe like), PKC inhibitors (e.g., LY-333531 and the like), AGE inhibitors(e.g., ALT946, pimagedine, pyratoxanthine, N-phenacylthiazolium bromide(ALT766), EXO-226 and the like), active oxygen scavengers (e.g.,thioctic acid and the like), cerebral vasodilators (e.g., tiapride,mexiletine and the like), and the like.

Examples of the antihyperlipemia agent include statin compounds whichare cholesterol synthesis inhibitors (e.g., cerivastatin, pravastatin,simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin andsalts thereof (e.g., sodium salt) and the like), squalene synthaseinhibitors (e.g., compounds described in WO97/10224, such asN-[-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzooxazepin-3-yl]acetyl]-piperidine-4-aceticacid and the like) or fibrate compounds having a triglyceride loweringaction (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate and thelike), ACAT inhibitors (e.g., Avasimibe, Eflucimibe and the like), anionexchange resins (e.g., colestyramine and the like), probucol, nicotinicacid drugs (e.g., nicomol, niceritrol and the like), ethyl icosapentate,plant sterols (e.g., soysterol, γ-oryzanol and the like) and the like.

Examples of the antihypertensive agent include angiotensin convertingenzyme inhibitors (e.g., captopril, enalapril, delapril and the like) orangiotensin II antagonists (e.g., candesartan cilexetil, losartan,eprosartan, valsartan, telmisartan, irbesartan, tasosartan and thelike), calcium antagonists (e.g., manidipine, nifedipine, amlodipine,efonidipine, nicardipine and the like), potassium channel, openers(e.g., levcromakalim, L-27152, AL 0671, NIP-121 and the like), Clonidineand the like.

Examples of the antiobestic agent include central antiobestic agents(e.g., Dexfenfluramine, fenfluramine, phentermine, Sibutramine,amfepramone, dexamphetamine, Mazindol, phenylpropanolamine, clobenzorexand the like), pancreatic lipase inhibitors (e.g., orlistat and thelike), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552,AJ-9677, BMS-196085, AZ40140and the like), peptide anorexiants (e.g.,leptin, CNTF (Ciliary Neurotropic Factor) and the like), cholecystokininagonists (e.g., lintitript, FPL-15849 and the like) and the like.

Examples of the diuretic include xanthine derivatives (e.g., sodiumsalicylate and theobromine, calcium salicylate and theobromine and thelike), thiazide preparations (e.g., ethiazide, cyclopenthiazide,trichloromethyazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, polythiazide, methylcothiazideand the like), antialdosterone agents (e.g., spironolactone, triamtereneand the like), carbonate dehydrating enzyme inhibitors (e.g.,acetazolamide and the like), chlorobenzenesulfonamide agents (e.g.,chlortalidone, mefruside, indapamide and the like), azosemide,isosorbide, etacrynic acid, piretanide, bumetanide, furosemide and thelike.

Examples of the chemotherapeutic agent include alkylation agents (e.g.,cyclophosphamide, ifosfamide and the like), metabolic antagonists (e.g.,methotrexate, 5-fluorouracil and the like), anti-cancer antibiotics(e.g., mitomycin, adriamycin and the like), plant-derived anti-canceragents (e.g., vincristin, vindesine, taxol and the like), cisplatin,carboplatin, etopoxide and the like. Of these, furtulon and neofurtulonwhich are 5-fluorouracil derivatives and the like are preferable.

Examples of the immunotherapeutic agent include microorganism orbacterial components (e.g., muramyl dipeptide derivative, picibanil andthe like), polysaccharides having immunity potentiating activity (e.g.,lentinan, sizofiran, krestin and the like), cytokines obtained bygenetic engineering techniques (e.g., interferon, interleukin (IL) andthe like), colony stimulating factors (e.g., granulocyte stimulatingfactor, erythropoietin and the like) and the like, with preference givento IL-1, IL-2, IL-12 and the like.

Examples of the antithrombotic agent include heparin (e.g., heparinsodium, heparin calcium, dalteparin sodium and the like), warfarin(e.g., warfarin potassium and the like), anti-thrombin drugs (e.g.aragatroban and the like), thrombolytic agents (eg., urokinase,tisokinase, alteplase, nateplase, monteplase, pamiteplase and the like),platelet aggregation inhibitors (e.g., ticlopidine hydrochloride,cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelatehydrochloride and the like) and the like.

Examples of the therapeutic agent of osteoporosis include alfacalcidol,calcitriol, elcaltonin, calcitonin salmon, estriol, ipriflavone,papidronate disodium, alendronate sodium hydrate, incadronate disodiumand the like.

Examples of the antidementia agent include tacrine, donepezil,rivastigmine, galantamine and the like.

Examples of the agent for improving erectile, dysfunction includeapomorphine, sildenafil citrate and the like.

Examples of the therapeutic agent of incontinentia or pollakiuriainclude flavoxate hydrochloride, oxybutynin hydrochloride, propiverinehydrochloride and the like.

Furthermore, drugs having a cachexia-improving action established inanimal models and clinical situations, such as cyclooxygenase inhibitors(e.g., Indometacin and the like) [Cancer Research, vol. 49, 5935–5939,1989], Progesterone derivatives (e.g., Megesterol acetate) [Journal ofClinical Oncology, vol. 12, 213–225, 1994], glucosteroid (e.g.,dexamethasone and the like), metoclopramide agents, tetrahydrocannabinolagents (ibid.), fat metabolism improving agents (e.g., eicosapentaenoicacid and the like) [British Journal of Cancer, vol. 68, 314–318, 1993],growth hormones, IGF-1, or antibodies to a cachexia-induced factor suchas TNF-α, LIF, IL-6, Oncostatin M and the like, can be used incombination with the compound of the present invention.

The combination drug is preferably an insulin preparation, an insulinsensitizer, an α-glucosidase inhibitor, a biguanide, an insulinsecretagogue (preferably a sulfonylurea) or the like.

Two or more of the above-mentioned combination drugs can be used incombination in an appropriate ratio. Preferable combinations in the caseof using two or more combination drugs are, for example, as shown in thefollowing.

-   (1) an insulin secretagogue (preferably a sulfonylurea) and an    α-glucosidase inhibitor;-   (2) an insulin secretagogue (preferably a sulfonylurea) and a    biguanide;-   (3) an insulin secretagogue (preferably a sulfonylurea), a biguanide    and an α-glucosidase inhibitor;-   (4) an insulin sensitizer and an a-glucosidase inhibitor;-   (5) an insulin sensitizer and a biguanide;-   (6) an insulin sensitizer, a biguanide and an α-glucosidase    inhibitor.

When the compound of the present invention or the pharmaceutical agentof the present invention is used in combination with a combination drug,the amount thereof can be reduced within a safe range in considerationof counteraction of these agents. Particularly, the dose of an insulinsensitizer, an insulin secretagogue (preferably a sulfonylurea) and abiguanide can be reduced as compared with the normal dose. Therefore, anadverse effect which may be caused by these agents can be preventedsafely. In addition, the dose of the therapeutic agent of diabeticcomplications, antihyperlipemia agent and antihypertensive agent can bereduced whereby an adverse effect which may be caused by these agentscan be prevented effectively.

Hereinafter the production methods of the compound of the presentinvention are explained.

The compound of the present invention can be produced according to amethod known per se, such as a method to be described in detail in thefollowing, or an analogous method thereto.

For example, compound (I-a) of the formula (I) wherein L is alkylene canbe produced according to the following Method A or an analogous methodthereto.

wherein La is a bond or alkylene, L¹ is a leaving group, and othersymbols are as defined above.

The alkylene for La is exemplified by that mentioned as theaforementioned L. When L is alkylene, L is the same as La(CH₂).

The leaving group for L¹ may be, for example, halogen atom (e.g.,chlorine, bromine, iodine and the like), optionally halogenated C₁₋₆alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy,trifluoromethanesulfonyloxy and the like), optionally substituted C₆₋₁₀arylsulfonyloxy, hydroxy and the like.

Examples of the substituent in the “optionally substituted C₆₋₁₀arylsulfonyloxy” include halogen atom (e.g., chlorine, bromine, iodineand the like), optionally halogenated C₁₋₆ alkyl or C₁₋₆ alkoxy and thelike. The number of the substituent(s) is, for example, 1 to 3. Specificexamples of the “optionally substituted C₆₋₁₀ arylsulfonyloxy” includebenzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy,2-naphthalenesulfonyloxy and the like.

The “leaving group” is preferably halogen atom (e.g., chlorine, bromine,iodine and the like), methanesulfonyloxy, trifluoromethanesulfonyloxy,p-toluenesulfonyloxy and the like.

(Step 1)

This reaction is carried out by directly reducing with a reducing agent(e.g., borane, lithium aluminum hydride and the like) in a solvent thatdoes not adversely influence the reaction, or converting a carboxylgroup to its reactive derivative (e.g., acid halide, mixed acidanhydride, active ester, ester and the like) and reducing with areducing agent (e.g., sodium borohydride, sodium lithium borohydride,lithium aluminum hydride, diisobutyl aluminum hydride and the like).

The amount of the reducing agent to be used is preferably from about 0.5to about 10 molar equivalents per compound (II).

The solvent that does not adversely influence the reaction variesdepending on the reducing agent. Examples thereof include aromatichydrocarbons such as benzene, toluene, xylene and the like; halogenatedhydrocarbons such as chloroform, dichlordmethane and the like; etherssuch as tetrahydrofuran, 1,2-dimethoxyethane, dioxane, diethyl ether andthe like; water; alcohols such as methanol, ethanol, isopropanol and thelike; and the like. Two or more of these solvents may be used uponmixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The compound (III) thus obtained can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

(Step 2)

When L¹ is a halogen atom, this reaction is carried out using ahalogenating agent in a solvent that does not adversely influence thereaction.

Examples of the halogenating agent include thionyl chloride, phosphorustribromide and the like.

The amount of the halogenating agent to be used is preferably 1 to about20 molar equivalents per compound (III).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like, and the like. Two or more of these solvents may be used uponmixing at a suitable ratio. It is also possible to use an excesshalogenating agent as a solvent.

The reaction temperature is generally from about −20° C. to about 150°C., preferably about 0° C. to about 100° C.

The reaction time is generally from about 0.1 to about 20 hours.

When L¹ is an optionally halogenated C₁₋₆ alkylsulfonyloxy or anoptionally substituted C₆₋₁₀ arylsulfonyloxy, this reaction is carriedout using a sulfonylating agent in the presence of a base in a solventthat does not adversely influence the reaction.

Examples of the sulfonylating agent include mesyl chloride, tosylchloride, benzenesulfonyl chloride and the like.

Examples of the base include amines such as triethylamine,N-methylmorpholine, N,N-dimethylaniline and the like; alkali metal saltssuch as sodium hydrogencarbonate, sodium carbonate, potassium carbonateand the like; and the like.

The amount of the sulfonylating agent and the base to be used ispreferably 1 to about 2 molar equivalents per compound (III).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; ethyl acetate and the like.

Two or more of these solvents may be used upon mixing at a suitableratio.

The reaction temperature is generally about −20° C. to about 150° C.,preferably about 0° C. to about 100° C.

The reaction time is generally from about 0.1 to about 20 hours.

The thus-obtained compound (IV) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

(Step 3)

This reaction is carried out by reacting compound (IV) and an aminatingagent in a solvent that does not adversely influence the reactions andsubjecting the obtained compound to deprotection of an amino group asnecessary.

Examples of the aminating agent include ammonia, hexamethylenetetramine,potassium phthalimide, di-t-butyl dicarboxylimide and the like.

The amount of the aminating agent to be used is preferably about 1 toabout 5 molar equivalents per compound (IV).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene, and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; alcohols such as methanol, ethanol, isopropanol and the like;ketones such as acetone, 2-butanone and the like; amides such asN,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; and the like. Two or more of these solvents maybe used upon mixing at a suitable ratio.

The reaction temperature is about 0° C. to about 200° C., preferablyabout 20° C. to about 120° C.

The reaction time is generally from about 0.5 to about 20 hours.

The amino group is deprotected according to a method known per se.

The thus obtained compound (I-a) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

The compound (II) used as a starting material compound in Method A canbe produced according to a method known per se, for example, the methodsdetailed in the following or analogous methods thereto.

The compound (II-a) which is a compound of the formula (II) wherein Lais a bond and X is —O— can be produced according to the method describedin, for example, Journal of Heterocyclic chemistry, vol. 7, 1057 (1970),the following Method B, or analogous methods thereto.

wherein R is a C₁₋₆ alkyl group, R¹⁰ is a hydrogen atom or an optionallysubstituted hydrocarbon group, L² is a leaving group and other symbolsare as defined above.

Examples of the C₁₋₆ alkyl group for R include methyl, ethyl and thelike.

The “optionally substituted hydrocarbon group” for R¹⁰ is exemplified bythat mentioned as the aforementioned R³.

The leaving group for L² is exemplified by that mentioned as theaforementioned L¹. The leaving group for L² maybe a hydroxy group.

(Step 4)

This reaction is carried out according to, for example a methodcomprising direct condensation of compound (V) and glycine derivative(X) using a condensation agent (e.g., dicyclohexylcarbodiimide and thelike), or a method comprising appropriately reacting a reactivederivative of compound (V) and a glycine derivative and the like.Examples of the reactive derivative include acid anhydride, acid halide(e.g., acid chloride, acid bromide), imidazolide, or mixed acidanhydride (e.g., anhydride with methyl carbonate, ethyl carbonate orisobutyl carbonate and the like) and the like.

When, for example, acid halide is used as a reactive derivative ofcompound (V), the reaction is carried out in the presence of a base in asolvent that does not adversely influence the reaction.

Examples of the base include amines such as triethylamine,N-methylmorpholine, N,N-dimethylaniline and the like; alkali metal saltssuch as sodium hydrogencarbonate, sodium carbonate, potassium carbonateand the like; and the like.

Examples of the solvent that does not adversely influence the reactioninclude halogenated hydrocarbons such as chloroform, dichloromethane andthe like; aromatic hydrocarbons such as benzene, toluene and the like;ethers such as tetrahydrofuran, dioxane, diethyl ether and the like;ethyl acetate, water and the like. Two or more of these solvents may beused upon mixing at a suitable ratio.

The amount of the glycine derivative (X) to be used is 0.1 to 10 molarequivalents preferably 1 to 3 molar equivalents, per compound (V).

The reaction temperature is about −30° C. to about 100° C.

The reaction time is generally 0.5 to 20 hours.

When a mixed acid anhydride is used as a reactive derivative of compound(V), compound (V) and chlorocarbonate ester (e.g., methylchlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate and thelike) are reacted in the presence of a base and then reacted withglycine derivative (X).

Examples of the base include amines such as triethylamine,N-methylmorpholine, N,N-dimethylaniline and the like; alkali metal saltssuch as sodium hydrogencarbonate, sodium carbonate, potassium carbonateand the like; and the like.

The amount of the glycine derivative (X) to be used is generally 0.1 to10 molar equivalents, preferably 0.3 to 3 molar equivalents, percompound (V).

The reaction temperature is generally from about −30° C. to about 100°C.

The reaction time is generally from 0.5 to 20 hours.

The thus-obtained compound (VI) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

The compound (V) and glycine derivative (X) used as a starting materialcompound in step 4 can be produced according to a method known per se.

(Step 5)

This reaction is carried out according to a conventional method in thepresence of a base in a solvent that does not adversely influence thereaction.

Examples of the base include metalhydrides such as sodium hydride,potassium hydride and the like; alkali metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium t-butoxide and the like; alkalimetal salts such as potassium hydroxide, sodium hydroxide, sodiumhydrogencarbonate, potassium carbonate and the like; amines such aspyridine, triethylamine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undeca-7-ene and the like.

The amount of the base to be used is preferably about 0.1 to about 2molar equivalents per compound(VI).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; water; alcohols such as methanol, ethanol, isopropanol and thelike; ketones such as acetone, 2-butanone and the like; amides such asN,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; and the like. Two or more of these solvents maybe used upon mixing at a suitable ratio.

The reaction temperature is about −10° C. to about 150° C., preferablyabout 0° C. to about 110° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (VII) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

(Step 6)

When L² is a hydroxy group, this reaction is carried, out by a methodknown per se, such as a method described in Synthesis, page 1 (1981), oran analogous method thereto.

This reaction is generally carried out in the presence of an organicphosphorus compound and electrophil in a solvent that does not adverselyinfluence the reaction.

Examples of the organic phosphorus compound include triphenylphosphine,tributylphosphine and the like.

Examples of the electrophil include diethyl azodicarboxylate,diisopropyl azodicarboxylate, azodicarbonyldipiperazine and the like.

The amount of the organic phosphorus compound and electrophil to be usedis preferably about 1 to about 5 molar equivalents per compound (VII).

Examples of the solvent that does not adversely influence the reactioninclude ethers such as diethyl ether, tetrahydrofuran, dioxane and thelike; halogenated hydrocarbons such as chloroform, dichloromethane, andthe like; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; amides such as N,N-dimethylformamide and the like; sulfoxides suchas dimethyl sulfoxide and the like; and the like. Two or more of thesesolvents may be used upon mixing at a suitable ratio.

The reaction temperature is about −50° C. to about 150° C., preferablyabout −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

When L² is a halogen atom, an optionally halogenated C₁₋₆alkylsulfonyloxy or an optionally substituted C₆₋₁₀ arylsulfonyloxy,this reaction is carried out according to a conventional method in thepresence of a base in a solvent that does not adversely influence thereaction.

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and the like;metalhydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium t.-butoxide and the like; and the like.

The amount of the base to be used is preferably about 1 to about 5 molarequivalents per compound (VII).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl, ether and thelike; ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; and the like. Two or more of these solvents maybe used upon mixing at a suitable ratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The compound obtained from the aforementioned step 6 is hydrolyzed,where necessary, by a method known per se to give compound (II-a).

The thus-obtained compound (II-a) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

The compound (VI) to be used in the aforementioned Method B can be alsoproduced according to the following Method C.

wherein the symbols are as defined above.(Step 7)

This reaction is carried out according to a conventional method in asolvent that does not adversely influence the reaction.

Examples of the solvent that does not adversely influence the reactioninclude halogenated hydrocarbons such as chloroform, dichloromethane andthe like; aromatic, hydrocarbons such as benzene, toluene and the like;ethers such as tetrahydrofuran, dioxane, diethyl ether and the like;ethyl acetate and the like. Two or more of these solvents may be usedupon mixing at a suitable ratio.

The amount of the glycine derivative (X) to be used is about 1 to about10 molar equivalents; preferably 1 to 3 molar equivalents per compound(VIII).

The reaction temperature is generally from −30° C. to 100° C.

The reaction time is generally from 0.5 to 20 hours.

The thus-obtained compound (IX) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced, pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

The compound (VIII) used as a starting material compound in Step 7 canbe produced according to a method known per se.

(Step 8)

This reaction is carried out according to a conventional method in thepresence of a base and a C₁₋₆ alkyl halide in a solvent that does notadversely influence the reaction.

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and the like.

The amount of the base to be used is preferably about 1 to about 2 molarequivalents per compound (IX).

Examples of the C₁₋₆ alkyl halide include iodomethane, iodoethane andthe like.

The amount of the C₁₋₆ alkyl halide to be used is preferably about 1 toabout 2 molar equivalents per compound (IX).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane, andthe like; ketones such as acetone, 2-butanone and the like; amides suchas N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; and the like. Two or more of these solvents maybe used upon mixing at a suitable ratio.

The reaction temperature is generally from about −10° C. to about 150°C., preferably 0° C., to 110° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (VI) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

The compound (II-b) which is a compound of the formula (II) wherein Lais a bond and X is a bond can be produced by a method described in, forexample, JP-A-7-76573, JP-A-2000-72751 or JP-A-2000-72675, the followingMethod D or analogous methods thereto.

wherein L³ is a leaving group, and other symbols are as defined above.

The leaving group for L³ is exemplified by that mentioned as theaforementioned L¹.

(Step 9)

When, for example, L³ is an optionally halogenated C₁₋₆ alkylsulfonyloxyor an optionally substituted C₆₋₁₀ arylsulfonyloxy, this reaction iscarried out according to a conventional method in the presence of a baseand a sulfonylating agent in a solvent that does not adversely influencethe reaction.

Examples of the base include metalhydrides such as sodium hydride,potassium hydride and the like; alkali metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium t-butoxide and the like; alkalimetal salts such as potassium hydroxide, sodium hydroxide, sodiumhydrogencarbonate, potassium carbonate and the like; amines such aspyridine, triethylamine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undeca-7-ene and the like.

The amount of the base to be used is preferably about 1 to about 5 molarequivalents per compound (VII).

Examples of the sulfonylating agent includeN-phenyltrifluoromethanesulfonimide, anhydrous trifluoromethanesulfonicacid and the like.

The amount of the sulfonylating agent to be used is preferably about 1to about 5 molar equivalents per compound (VII).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; and the like. Two or more of these solvents may be used uponmixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably about −10° C. to about 20° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (XI) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

(Step 10)

This reaction is carried out according to a conventional method in thepresence of a base, and a metal catalyst in a solvent that does notadversely influence the reaction under an inert gas atmosphere.

Examples of the base include metalhydrides such as sodium hydride,potassium hydride and the like; akali metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium t-butoxide and the like; alkalimetal salts such as potassium hydroxide, sodium hydroxide, sodiumhydrogencarbonate, sodium carbonate, potassium carbonate and the like;amines such as pyridine, triethylamine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undeca-7-ene and the like. Of these, alkali metalsalts such as sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate and the like are preferable.

The amount of the base to be used is preferably about 1 to about 5 molarequivalents per compound (XI).

Examples of the metal catalyst include palladium complex such astetrakis(triphenylphosphine)palladium(0) and the like.

The amount of use of the metal catalyst is preferably about 0.01 toabout 0.5 molar equivalents per compound (XI).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; water; alcohols such as methanol, ethanol, isopropanol and thelike; ketones such as acetone, 2-butanone and the like; amides such asN,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; and the like. Two or more of these solvents maybe used upon mixing at a suitable ratio.

Examples of the inert gas include argon, nitrogen and the like.

The reaction temperature is generally from about −10° C. to about 150°C., preferably about 0° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The compound obtained from Step 10 is hydrolyzed according to a methodknown per se to give compound (II-b).

The compound (II-b) can be isolated and purified by a known separationand purification means, such as concentration, concentration underreduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

The compound (I-aa) wherein ring A has a group of the formula: —CO—OR⁴(R⁴ is as defined above) as a substituent can be also produced by thefollowing Method E.

wherein L⁴ is a leaving group, Boc is a t-butoxycarbonyl group and othersymbols are as defined above.

The leaving group for L⁴ is exemplified by that mentioned as theaforementioned L¹.

(Step 11)

This reaction is carried out in the presence of carbon monoxide, a metalcatalyst, a reaction reagent and an alcohol in a solvent that does notadversely influence the reaction.

The metal catalyst is, for example, a palladium catalyst (e.g.,palladium acetate and the like).

The amount of the metal catalyst to be used is preferably about 0.01toabout 1 molar equivalent per compound (XII).

The reaction reagent is, for example, an organic phosphorus compound(e.g., 1,3-bis(diphenylphosphino)propane and the like), a base (e.g.,amines such as pyridine, triethylamine, N,N-dimethylaniline etc., andthe like), and the like.

The amount of the reaction reagent to be used is preferably about 1 toabout 5 molar equivalents per compound (XII).

As the alcohol, an excess amount of ethanol or methanol is generallyused.

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide and the like; and the like. Two or more ofthese solvents may be used upon mixing at a suitable ratio.

The reaction temperature is generally from about 0° C. to about 150° C.,preferably about 50° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

From compound (XII-a) obtained from Step 11, Boc group is removed by amethod known per se to give compound (I-aa).

The thus-obtained compound (I-aa) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

The compound (XII) used as a starting material compound in Method E canbe produced according to, for example, the aforementioned Method A or ananalogous method thereto.

The compound (I-ab) wherein ring A has an optionally substituted hydroxygroup as a substituent can be also produced by the following Method F.

wherein L⁵ and L⁶ are leaving group, R¹² is an optionally substitutedhydrocarbon group and other symbols are as defined above.

The leaving group for L⁵ and L⁶ are exemplified by that mentioned as theaforementioned L¹.

Examples of the “optionally substituted hydrocarbon group” for R¹²include each optionally substituted “alkyl group having 1 to 10 carbonatom(s)”, “alkenyl group having 2 to 10 carbon atoms”, “alkynyl grouphaving 2 to 10 carbon atoms”, “cycloalkyl group, having 3 to 10 carbonatoms”, “cycloalkenyl group having 3 to 10 carbon atoms”, “aryl grouphaving 6 to 14 carbon atoms” and “aralkyl having 7 to 13 carbon atoms”mentioned in the “optionally substituted hydroxy group” as thesubstituent in ring A.

(Step 12)

This reaction is carried out using benzyl alcohol in the presence of abase in a solvent that does not adversely influence the reaction.

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and the like;metalhydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium t.-butoxide and the like; and the like.

The amount of the base to be used is preferably about 1 to about 5molarequivalents per compound (XII).

The amount of benzyl alcohol to be used is preferably about 1 to about 3molar equivalents per compound (XIII).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide and the like; and the like. Two or more ofthese solvents may be used upon mixing at a suitable ratio.

The reaction temperature is generally from about 0° C. to about 150° C.,preferably about 50° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (XIII-a) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

(Step 13)

This reaction is carried out by introducing a Boc group according to amethod known per se after reaction in the same manner as in theaforementioned Steps 1 to 3.

The thus-obtained compound (XII-b) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

(Step 14)

This reaction is carried out according to a per se known hydrogenationunder a hydrogen atmosphere or in the presence of a hydrogen source,such as formic acid and the like and a metal catalyst in a solvent thatdoes not adversely influence the reaction.

Examples of the metal catalyst include a transition metal catalyst suchas palladium-carbon, palladium black, platinum oxide, Raney-nickel,Wilkinson's catalyst etc., and the like.

The amount of the metal catalyst to be used is preferably about 0.01 toabout 10 molar equivalents per compound (XII-b).

Examples of the solvent that does not adversely influence the reactioninclude lower organic acids such as acetic acid and the like; etherssuch as tetrahydrofuran, dioxane, diethyl ether and the like; amidessuch as N,N-dimethylformamide and the like; alcohols such as methanol,ethanol, isopropanol and the like; and the like. Two or more of thesesolvents may be used upon mixing at a suitable ratio.

The reaction temperature is generally from about 0° C. to about 150° C.,preferably about 0° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (XII-c) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

(Step 15)

This Step is carried out by the reaction in the same manner as in theaforementioned Step 8.

The thus-obtained compound (XII-d) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

The compound (I-ab,) can be produced by removing a Boc group fromcompound (XII-d) according to a method known per se.

The compound (I-ab) can be isolated and purified by a known separationand purification means, such as concentration, concentration underreduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

The compound (XIII) used as a starting material compound in Method F canbe produced according to, for example, the aforementioned Method A or ananalogous method thereto.

The compound (I-ac) wherein ring A has an optionally substituted aminogroup as a substituent can be also produced according to the followingMethod G.

wherein R¹³ is a hydrocarbon group or an acyl group and other symbolsare as defined above.

Examples of the “hydrocarbon group” for R¹³ include “alkyl group having1 to 10 carbon atom(s)”, “alkenyl group having 2 to 10 carbon atoms”,“cycloalkyl group having 3 to 10 carbon atoms”, “cycloalkenyl grouphaving 3 to 10 carbon atoms” and “aryl group having 6 to 14 carbonatoms” mentioned in the “optionally substituted amino group” as thesubstituent in ring A. Examples of the acyl group for R¹³ is exemplifiedby that mentioned as the substituent in ring A.

(Step 16)

In this Step, compound (XII-e) and diphenylphosphoryl azide are reactedin the presence of a base in a solvent that does not adversely influencethe reaction to give an acyl azide compound, which is subjected toCurtius rearrangement reaction to give isocyanic acid derivative(XII-f).

The amount of the diphenylphosphoryl azide to be used is 1 to 10 molarequivalent(s), preferably 1.5 to 3 molar equivalents, per compound(XII-e).

Examples of the base include amines such as triethylamine,4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamineand the like.

The amount of the base to be used is preferably about 1 to about 5 molarequivalents per compound (XII-e).

Examples of the solvent that does not adversely influence the reactioninclude ethers such as diethyl ether, tetrahydrofuran, dioxane and thelike; halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform and the like; dimethylformamide and the like. Two or more ofthese solvents may be used upon mixing at a suitable ratio.

The reaction temperature is −20° C. to 50° C., preferably 0° C. to 20°C.

The reaction time is from 0.5 to 5 hours, preferably from 1 to 2 hours.

The Curtius rearrangement reaction is carried out according to a methodknown per se in a solvent that does not adversely influence thereaction.

Examples of the solvent that does not adversely influence the reactioninclude hydrocarbons such as benzene, toluene, xylene and the like;ethers such as diethyl ether, tetrahydrofuran, dioxane and the like;halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform and the like; amides such as dimethylformamide and the like;and the like. Two or more of these solvents may be used upon mixing at asuitable ratio.

The reaction temperature is generally from 50° C. to 200° C., preferably80° C. to 150° C.

The reaction time is generally from 0.5 to 12 hours, preferably from 1to 3 hours.

The thus-obtained compound (XII-f) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

(Step 17)

This reaction is carried out in a solvent that does not adverselyinfluence the reaction.

The amount of a compound of the formula: R⁴—OH (wherein the symbols areas defined above) to be used is preferably about 1 to about 5 molarequivalents per compound (XII-f).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide and the like; and the like. Two or more ofthese solvents may be used upon mixing at a suitable ratio.

The reaction temperature is generally from about 0° C. to about 150° C.,preferably about 50° C. to about 100° C.

The reaction time is generally from about 5 to about 20 hours.

This reaction may be carried out in the presence of a catalytic amountof N,N-dimethylaminopyridine and the like.

The thus-obtained compound (XII-g) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

By using a compound of the formula: HNR^(4a)R^(5a) (wherein the symbolsare as defined above) instead of a compound of the above-mentionedformula: R⁴—OH (wherein the symbols are as defined above), a compound(XII-g) wherein the substituent: R⁴OCONH— is replaced byR^(4a)R^(5a)NCONH— can be produced.

(Step 18)

This reaction is carried out by deprotection (e.g., catalytic reduction,piperidine treatment and the like) generally employed in peptidechemistry and the like.

The thus-obtained compound (XII-h) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

(Step 19)

This reaction is carried out according to a conventional method using analkylation agent, an acylation agent and the like in the presence of acondensation agent or a base in a solvent that does not adverselyinfluence the reaction.

The alkylation agent is exemplified by alkyl halides, alkylsulfonatesand the like.

The amount of the alkylation agent to be used is preferably about 1 toabout 5 molar equivalents per compound (XII-h).

The acylation agent is exemplified by carboxylic acid sulfonic acid,phosphoric acid, carbonic acid or reactive derivatives thereof (e.g.,acid halide, acid anhydride, mixed acid anhydride, active ester and thelike), isocyanide, isothiocyanide and the like.

The amount of the acylating agent to be used is preferably about 1 toabout 5 molar equivalents per compound (XII-h).

The condensation agent is exemplified by dicyclohexylcarbodiimide,diethyl cyanophosphate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideand the like.

The amount of the condensation agent to be used is preferably about 1 toabout 5 molar equivalents per compound (XII-h).

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and the like;metalhydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium t.-butoxide and the like; and the like.

The amount of the base to be used is preferably about 1 to about 5 molarequivalents per compound (XII-h).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane, and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; and the like. Two or more of these solvents maybe used upon mixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 50°C., preferably about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (XII-i) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

By removing a Boc group from the thus-obtained compound (XII-i)according to a method known per se, compound (I-ac) can be produced.

The compound (I-Ac) can be isolated and purified by a known separationand purification means, such as concentration, concentration underreduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

Furthermore, by removing a Boc group from the aforementioned compound(XII-g) and compound (XII-h) according to a method known per se, acompound (I-ac) wherein the substituent: R¹³HN— is respectivelysubstituted by R⁴OCONH— or amino can be produced.

The compound (XII-e) used as a starting material in Method G can beproduced according to, for example, the aforementioned Method A, MethodE or analogous methods thereto.

The compound (I-ae) which is a compound of the formula (I) wherein ringA has a carbamoyl group as a substituent and L is methylene can be alsoproduced by, for example, the following Method H.

wherein the symbols are as defined above.

The hydrolysis can be generally carried out in the presence of an acidor a base.

Examples of the acid include mineral acids (e.g., hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid and the like),carboxylic acids (e.g., formic acid, acetic acid, propionic acid and thelike), and the like. Of these, hydrochloric acid, sulfuric acid and thelike are preferable.

Examples of the base include alkali metal salts such as lithiumhydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate,sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonateand the like; alkaline earth metal salts such as calcium hydroxide,barium hydroxide and the like; amines such as trimethylamine,triethylamine, ethyldiisopropylamine, N-methylmorpholine and the like;and the like. Of these, potassium hydroxide, sodium hydroxide and thelike are preferable.

The amount of the acid or base to be used is, for example, 0.01 to 100molar equivalents, preferably 0.1 to 50 molar equivalents per compound(I-ad).

Hydrolysis is generally conducted in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include alcohols such asmethanol, ethanol, propanol, 2-propanol, butanol, isobutanol,tert-butanol and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; aliphatic hydrocarbons such as hexane,heptane and the like; ethers such as diethyl ether, diisopropyl ether,tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane andthe like; amides such as dimethylformamide, dimethylacetamide and thelike; sulfoxides such as dimethyl sulfoxide and the like; water and thelike. Two or more of these solvents may be used upon mixing at asuitable ratio.

The reaction temperature is generally from 0° C. to 150° C., preferably10° C. to 100° C.

The reaction time is generally from 0.1 to about 100 hours, preferablyfrom 0.1 to 10 hours.

The thus-obtained compound (I-ae) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

The compound (I-ad) used as a starting material compound in Method H canbe produced according to, for example, the following Method I.

wherein the symbols are as defined above.

In this method, compound (XVI) and compound (XVII) are reacted to givecompound (XV).

This reaction is carried out according to a per se known amidationreaction. This method may be, for example, a method comprising directcondensation of compound (XVI) and compound (XVII) using a condensationagent, a method comprising reacting a reactive derivative of compound(XVI) and compound (XVII), and the like.

Examples of the condensation agent include carbodiimide condensationreagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and its hydrochloride, andthe like; phosphoric acid condensation reagents such as diethylcyanophosphate, diphenylphosphoryl azide and the like;carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborateand the like.

Examples of the solvent to be used for a reaction using a condensationagent include amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone and the like; sulfoxides suchas dimethyl sulfoxide and the like; halogenated hydrocarbons such aschloroform, dichloromethane and the like; aromatic hydrocarbons such asbenzene, toluene and the like; ethers such as tetrahydrofuran, dioxane,diethyl ether, dimethoxyethane and the like; esters such as methylacetate, ethyl acetate and the like; nitriles such as acetonitrile,propionitrile and the like; water and the like. Two or more of thesesolvents may be used upon mixing at a suitable ratio.

The amount of the compound (XVII) to be used is generally 1 to 10 molarequivalents, preferably 1 to 3 molar equivalents, per compound (XVI).

The amount of the condensation agent to be used is generally 0.1 to 10molar equivalents, preferably 0.3 to 3 molar equivalents, per compound(XVI).

When a carbodiimide condensation reagent is used as a condensationagent, the reaction efficiency can be increased by the use of a suitablecondensation promoter (e.g., 1-hydroxy-7-azabenzotriazole,1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide andthe like) as necessary. When a phosphoric condensation reagent is usedas a condensation agent, the reaction efficiency can be increased by theuse of an organic amine base such as triethylamine and the like.

The amount of the above-mentioned condensation promoter and organicamine base to be used is generally 0.1 to 10 molar equivalents,preferably 0.3 to 3 molar equivalents, per compound (XVI).

The reaction temperature is generally from −30° C. to 120° C.,preferably −10° C. to 100° C.

The reaction time is generally from 0.5 to 60 hours.

The reactive derivative of compound (XVI) may be, for example, acidanhydride, acid halide (acid chloride, acid bromide), imidazolide, mixedacid anhydride (e.g., anhydride with methylcarbonate, ethylcarbonate orisobutylcarbonate and the like) and the like.

When, for example, an acid anhydride or an acid halide is used, thereaction is generally carried out in the presence of a base in a solventthat does not adversely influence the reaction.

Examples of the base include amines such as triethylamine, pyridine,N-methylmorpholine, N,N-dimethylaniline, 4-dimethylaminopyridine and thelike; alkali metal salts such as lithium hydroxide, sodium hydroxide,potassium hydroxide, sodium hydrogencarbonate, sodium carbonate,potassium carbonate and the like; and the like.

Examples of the solvent that does not adversely influence the reactioninclude amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone and the like, sulfoxides such as dimethyl sulfoxideand the like; halogenated hydrocarbons such as chloroform,dichloromethane and the like; aromatic hydrocarbons such as benzene,toluene and the like; ethers such as tetrahydrofuran, dioxane, diethylether, dimethoxyethane and the like; esters such as methyl acetate,ethyl acetate and the like; nitriles such as acetonitrile, propionitrileand the like; water and the like. Two or more of these solvents may beused upon mixing at a suitable ratio.

When the above-mentioned amides are used as the solvent that does notadversely influence the reaction, the reaction may be carried out in theabsence of a base.

The amount of the compound (XVII) to be used is generally 1 to 10 molarequivalents, preferably 1 to 5 molar equivalents, per compound (XVI).

The amount of the base to be used is generally 1 to 10 molarequivalents, preferably 1 to 5 molar equivalents per compound (XVI).

The reaction temperature is generally from −30° C. to 100° C.,preferably −10° C. to 100° C.

The reaction time is generally from 0.5 to 30 hours.

When a mixed acid anhydride is used, compound (XVI) and chlorocarbonate(e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutylchlorocarbonate and the like) are reacted in the presence of a base, andthe obtained compound is reacted with compound (XVII).

Examples of the base include amines such as triethylamine, aniline,N-methylmorpholine, N,N-dimethylaniline, 4-dimethylaminopyridine and thelike; alkali metal salts such as sodium hydroxide, potassium hydroxide,lithium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate and the like; and the like.

The amount of the compound (XVII) to be used is generally 1 to 10 molarequivalents, preferably 1 to 5 molar equivalents, per compound (XVI).

The amount of the base to be used is generally 1 to 10 molarequivalents, preferably 1 to 3 molar equivalents per compound (XVI).

The reaction temperature is generally from −30° C. to 120° C.,preferably −10° C. to 100° C.

The reaction time is generally from 0.5 to 20 hours.

The thus-obtained compound (XV) can be isolated and purified by a knownseparation and purification means such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like. It isalso possible to subject a reaction mixture containing compound (XV) tothe next reaction without isolating compound (XV).

The compound (XIV) is produced by subjecting the compound (XV) to a ringclosure reaction.

The ring closure reaction is generally carried out in the presence of abase in a solvent that does not adversely influence the reaction.

Examples of the base include amines such as triethylamine, pyridine,N-methylmorpholine, N,N-dimethylaniline, 4-dimethylaminopyridine,1,5-diazabicyclo[4.3.0]-5-nonene (DBN),1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and the like; alkali metalsalts such as lithium hydroxide, sodium hydroxide, potassium hydroxide,sodium hydrogencarbonate, sodium carbonate, potassium carbonate and thelike; and the like.

Examples of the solvent that does not adversely influence the reactioninclude amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone and the like; sulfoxides such as dimethyl sulfoxideand the like; halogenated hydrocarbons such as chloroform,dichloromethane and the like; aromatic hydrocarbons such as benzene,toluene and the like; ethers such as tetrahydrofuran, dioxane, diethylether, dimethoxyethane and the like; esters such as methyl acetate,ethyl acetate and the like; nitriles such as acetonitrile, propionitrileand the like; water and the like. Two or more of these solvents may beused upon mixing at a suitable ratio.

The amount of the base to be used is generally 0.01 to 10 molarequivalents, preferably 0.1 to 3 molar equivalents per compound (XV).

The reaction temperature is generally from −30° C. to 120° C.,preferably −10° C. to 100° C.

The reaction time is generally from 0.5 to 40 hours.

The thus-obtained compound (XIV) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like. It isalso possible to subject a reaction mixture containing compound (XIV) tothe next reaction without isolating compound (XIV).

The compound (I-af) is produced by reducing compound (XIV).

The reduction is performed according to a conventional method in thepresence of a reducing agent in a solvent that does not adverselyinfluence the reaction.

Examples of the reducing agent include metal hydrogen compounds such asbis(2-methoxyethoxy)aluminum sodium hydride, diisobutyl aluminum hydrideand the like; metal hydrogen complex compounds such as sodiumborohydride, sodium cyanide borohydride, aluminum lithium hydride,aluminum sodium hydride and the like; and the like.

The amount of the reducing agent to be used is generally 0.1 to 20 molarequivalents per compound (XIV).

Examples of the solvent that does not adversely influence the reactioninclude alcohols such as methanol, ethanol, propanol, 2-propanol,butanol, isobutanol, tert-butanol and the like; aromatic hydrocarbonssuch as benzene, toluene, xylene and the like; aliphatic hydrocarbonssuch as hexane, heptane and the like; ethers such as diethyl ether,diisopropyl ether, tert-butylmethyl ether, tetrahydrofuran, dioxane,dimeithoxyethane and the like; esters such as methyl acetate, ethylacetate, n-butyl acetate, tert-butyl acetate and the like; amides suchas dimethylformamide, dimethylacetamide, N-methylpyrrolidone and thelike. Two or more of these solvents may be used upon mixing at asuitable ratio.

The reaction temperature is generally from −70° C. to 150° C.,preferably −20° C. to 100° C.

The reaction time is generally from 0.1 to 100 hours, preferably from0.1 to 40 hours.

The reduction reaction can be also conducted in the presence of a metalcatalyst such as palladium-carbon, palladium black, palladium chloride,platinum oxide, platinum black, platinum-palladium, Raney-nickel,Raney-cobalt and the like, and a hydrogen source in a solvent that doesnot adversely influence the reaction.

The amount of the metal catalyst to be used is generally 0.001 to 1000molar equivalents, preferably 0.01 to 100 molar equivalents, percompound (XIV).

Examples of the hydrogen source include hydrogen gas, formic acid,formic acid amine salt, phosphinate, hydrazine and the like.

The solvent that does not adversely influence the reaction is thatemployed for reduction using the aforementioned reducing agent.

The reaction temperature and reaction time are the same as those forreduction using the aforementioned reducing agent.

This reaction may be carried out in the presence of ammonia (e.g.,aqueous ammonia, ammonia-ethanol and the like) as necessary. By reactingin the presence of ammonia, side reaction is suppressed and compound(I-af) can be produced in a high yield.

The thus-obtained compound (I-af) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like. It is also possible to subject a reaction mixture containingcompound (I-af) to the next reaction without isolating compound (I-af).

The compound (I-ad) is produced by reacting compound (I-af)and a metalcyanide.

Examples of the metal cyanide include potassium cyanide, sodium cyanide,zinc cyanide and the like.

The reaction is generally carried out in a solvent that does notadversely influence the reaction.

Examples of the solvent that does not adversely influence the reactioninclude amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone and the like; sulfoxides such as dimethyl sulfoxideand the like; halogenated hydrocarbons such as chloroform,dichloromethane and the like; aromatic hydrocarbons such as benzene,toluene and the like; ethers such as tetrahydrofuran, dioxane, diethylether, dimethoxyethane and the like; esters such as methyl acetate,ethyl acetate and the like; nitriles such as acetonitrile, propionitrileand the like; water and the like. Two or more of these solvents may beused upon mixing at a suitable ratio.

In this reaction, a catalyst may be used where necessary. Examples ofthe catalyst include transition metal compounds such as rhodium,palladium-carbon, tetrakis(triphenylphosphine)palladium,tetrakis(tri-(2-toryl)phosphine)palladium,tetrakis(tri-(2-furyl)phosphine)palladium, bis(acetylacetone)nickel,dichlorobis(triphenylphosphine)nickel, bis(1,5-cyclooctadiene)nickel,bis(1,10-phenanthroline)nickel, Raney-nickel, Raney-cobalt and the like.

The amount of the metal cyanide to be used is generally 1 to 100 molarequivalents, preferably 1 to 10 molar equivalents, per compound(I-af).

The amount of the catalyst to be used is generally 0.00001 to 10 molarequivalents, preferably 0.001 to 1 molar equivalent, per compound(I-af).

The reaction temperature is generally from, −10° C. to 250° C.,preferably 0° C. to 150° C.

The reaction time is generally from 0.1 to 100 hours, preferably 0.1 to40 hours.

The thus-obtained compound (I-ad) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

The compound (XVI) used as a starting material compound in Method I canbe produced according to a method known per se.

In each of the aforementioned reactions, when the starting materialcompound has amino, carboxy, hydroxy or carbonyl as a substituent, aprotecting group generally known in peptide chemistry and the like maybe introduced into these groups. By removing the protecting group asnecessary after the reaction, the objective compound can be obtained.

The amino-protecting group includes, for example, formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl and the like), C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl and the like), benzoyl, C₇₋₁₃ aralkyl-carbonyl(e.g., benzylcarbonyl and the like), C₇₋₁₃ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl and the like), trityl,phthaloyl, N,N-dimethylaminomethylene, silyl (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldimethylsilyl and the like), C₂₋₆ alkenyl(e.g., 1-allyl andthe like) and the like. These groups are optionally substituted by 1 to3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine and thelike), C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy and the like) ornitro and the like.

The carboxy-protecting group is, for example, C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, tert-butyl and the like), C₇₋₁₃ aralkyl(e.g., benzyl and the like), phenyl, trityl, silyl (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like), C₂₋₆alkenyl (e.g., 1-allyl and the like) and the like. These groups areoptionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine,chlorine, bromine, iodine and the like), C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy and the like) or nitro and the like.

The hydroxy-protecting group is, for example, C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl,trityl, C₇₋₁₃ aralkyl (e.g., benzyl and the like), formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl and the like), benzoyl, C₇₋₁₃aralkyl-carbonyl (e.g., benzylcarbonyl and the like),2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl and the like), C₂₋₆ alkenyl (e.g., 1-allyl andthe like) and the like. These groups are optionally substituted by 1 to3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine and thelike), C₁₋₆ alkyl (e.g., methyl, ethyl, propyl and the like), C₁₋₆alkoxy (e.g., methoxy, ethoxy, propoxy and the like) or nitro and thelike.

The carbonyl-protecting group is, for example, cyclic acetal (e.g.,1,3-dioxane and the like), non-cyclic acetal (e.g., di-C₁₋₆ alkyl acetaland the like) and the like.

Introduction and removal of these protecting groups can follow a methodknown per se, for example, a method described in Protective Groups inOrganic Synthesis, John Wiley and Sons (1980) and the like. For example,employed is a method using acid, base, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride,palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide,trimethylsilyl bromide and the like) and the like, reduction and thelike.

When the starting material compound can form a salt in each of theaforementioned reactions, the compound in the form of a salt may beused. The salt is, for example the salt of compound (I) exemplifiedabove.

When compound (I) contains an optical isomer, a stereoisomer, apositional isomer or a rotational isomer, these are also encompassedcompound (I), and can be obtained as a single product according to asynthetic method and separation method known per se. For example, whencompound (I) contains an optical isomer, an optical isomer resolved fromthis compound is also encompassed in compound (I).

The optical isomer can be produced by a method known per se. To bespecific, an optically active synthetic, intermediate used, or the finalracemate product is subjected to optical resolution according to aconventional method to give an optical isomer.

The method of optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method and the like.

1) Fractional Recrystallization Method

A salt of a racemate with an optically active compound (e.g.,(+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaricacid, (+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine,(−)-cinchonidine, brucine and the like) is formed, which is separated bya fractional recrystallization method, and a free optical isomer isobtained by a neutralization step where desired.

2) Chiral Column Method

A racemate or a salt thereof is applied to a column for separation of anoptical isomer (chiral column) to allow separation. In the case of aliquid chromatography, for example, a mixture of an optical isomer isapplied to a chiral column such as ENANTIO-OVM (manufactured by TosohCorporation) or CHIRAL series (manufactured by Daicel ChemicalIndustries, Ltd.) and the like, and developed with water, variousbuffers (e.g., phosphate buffer) and organic solvents (e.g., ethanol,methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamineand the like) solely or in admixture to separate the optical isomer. Inthe case of a gas chromatography, for example, a chiral column such asCP-Chirasil-DeX CB (manufactured by GL Sciences Inc.) and the like isused to allow separation.

3) Diastereomer Method

A racemate mixture is prepared into a diastereomer mixture by chemicalreaction with an optically active reagent, which is prepared into ahomogeneous substance by a typical separation means (e.g., fractionalrecrystallization, chromatography method and the like), and the like,and subjected to a chemical treatment such as hydrolysis and the like toseparate the optically active reagent moiety, whereby an optical isomeris obtained. For example, when compound (I) contains hydroxy or primaryor secondary amino in a molecule, the compound and an optically activeorganic acid (e.g., MTPA [α-methoxy-α-(trifluoromethyl)phenylaceticacid], (−)-menthoxyacetic acid and the like) and the like are subjectedto condensation to give an ester form or amide form diastereomer. Whencompound (I) has a carboxylic acid group, this compound and an opticallyactive amine or an alcohol reagent are subjected to condensation to givean ester form or amide form diastereomer. The separated diastereomer isconverted to an optical isomer of the original compound by acidhydrolysis or base hydrolysis.

The compound (I) and a salt thereof may be in the form of a crystal.

The crystal of compound (I) or a salt thereof (hereinafter sometimes tobe referred to as crystal of the present invention) can be produced bycrystallization of compound (I) or a salt thereof by a crystallizationmethod known per se.

Examples of the crystallization method include crystallization from asolution, crystallization from vapor, crystallization from a molten formand the like.

The “crystallization method from a solution” is typically a methodincluding shifting a non-saturation state to hyper-saturation state byvarying factors involved in solubility of compounds (solventcomposition, pH, temperature, ionic strength, oxidation-reduction stateand the like) or the amount of solvent. To be specific, for example,concentration method, annealing method, reaction method (diffusionmethod, electrolysis method), hydrothermal growth method, fusing agentmethod and the like can be mentioned. Examples of the solvent to be usedinclude aromatic hydrocarbons (e.g., benzene, toluene, xylene and thelike), halogenated hydrocarbons (e.g., dichloromethane, chloroform andthe like), saturated hydrocarbons (e.g., hexane, heptane, cyclohexaneand the like), ethers (e.g., diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane and the like), nitriles (e.g., acetonitrile andthe like), ketones (e.g., acetone and the like), sulfoxides (e.g.,dimethyl sulfoxide and the like), acid amides (e.g.,N,N-dimethylformamide and the like), esters (e.g., ethyl acetate and thelike), alcohols (e.g., methanol, ethanol, isopropyl alcohol and thelike), water and the like. These solvents are used alone or incombination of two or more at a suitable ratio (e.g., 1:1 to 1:100(volume ratio)).

The “crystallization method from vapor” is, for example, vaporizationmethod (sealed tube method, gas stream method), gas phase reactionmethod, chemical transportation method and the like.

The “crystallization method from a molten form” is, for example, normalfreezing method (Czockralski method, temperature gradient method,Bridgman method), zone melting method (zone leveling method, floatingzone method), special growth method (VLS method, liquid phase epitaxymethod) and the like.

Preferable examples of the crystallization method include a methodincluding dissolving compound (I) or a salt thereof in a suitablesolvent (e.g., alcohols such as methanol, ethanol etc., and the like) ata temperature of 20–120° C. and cooling the resulting solution to atemperature not higher than a the temperature of dissolution (e.g.,0–50° C., preferably 0–20° C.) and the like.

The thus-obtained crystals of the present invention can be isolated by,for example, filtration and the like.

In the present specification, the melting point refers to that measuredusing, for example, micromelting point measuring apparatus (Yanako,MP-500D) or DSC (differential scanning calorimetry) device (SEIKO,EXSTAR6000) and the like.

In the present specification, moreover, a peak by powder X-raydiffraction refers to that measured using, for example, RINT2100 (RigakuIndustrial Corporation) and the like using Cu-Kα1 ray (tube voltage: 40KV; tube current: 50 mA) as a ray source.

In general, melting points and peaks by powder X-ray diffraction varydepending on measurement apparatuses, measurement conditions and thelike. The crystal in the present specification may show a differentmelting point or a peak by powder X-ray diffraction described in thepresent specification, as long as it is within general error range.

The crystal of the present invention is superior in physicochemicalproperties (e.g., melting point, solubility, stability and the like) andbiological properties (e.g., pharmacokinetics (absorption, distribution,metabolism, excretion), efficacy expression and the like), and isextremely useful as a pharmaceutical agent.

The present invention is explained in more detail by the followingExamples, Reference Examples, Experimental Examples and FormulationExamples. These do not limit the present invention and the presentinvention can be modified within the range that does not, deviate fromthe scope of the invention.

The abbreviations in Examples and Reference Examples mean the following.s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt:double triplet, m: multiplet, bs: broad singlet, tt: triple triplet, J:coupling constant, room temperature: 0–30° C.

EXAMPLES Example 13-(Aminomethyl)-4-butoxy-6-ethoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) A solution of 4-fluorophthalic anhydride (8.31 g, 50 mmol) and ethyl2-(neopentylamino)acetate (10.40 g, 60 mmol) in tetrahydrofuran (50 ml)was stirred at room temperature for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide (50ml), and potassium carbonate (6.91 g, 50 mmol) and ethyl iodide (4.8 ml,60 mmol) were added. The mixture was stirred at room temperature for 3h. The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in ethanol (50 ml) and 20% sodium ethoxide ethanolsolution (34.04 g, 100 mmol) was added. The mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into 1Nhydrochloric acid (150 ml) and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue, was purified by silicagel column chromatography and the component eluted earlier wasconcentrated to give ethyl7-fluoro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(5.12 g, 31.9%) as crystals.

Melting point 92–93° C. Elemental analysis for C₁₇H₂₀NO₄F Calculated: C,63.54; H, 6.27; N, 4.36. Found: C, 63.56; H, 6.19; N, 4.16.¹H-NMR(CDCl₃) δ: 0.85 (9H, s), 1.47 (3H, t, J=7.1 Hz), 4.48 (2H, q,J=7.1 Hz), 4.54 (2H, bs), 7.42–7.52 (1H, m), 8.10 (1H, dd, J=2.7, 9.2Hz), 8.17 (1H, dd, J=5.5, 9.2 Hz), 10.19 (1H, s).

The component eluted later was concentrated to give ethyl6-fluoro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(3.85 g, 24.0%) as crystals.

Melting point 115–115.5° C. Elemental analysis for C₁₇H₂₀NO₄FCalculated: C, 63.54; H, 6.27; N, 4.36. Found: C, 63.54; H, 6.19; N,4.11. ¹H-NMR(CDCl₃) δ: 0.85 (9H, s), 1.47 (3H, t, J=7.2 Hz), 4.49 (2H,q, J=7.2 Hz), 4.54 (2H, bs), 7.32–7.42 (1H, m), 7.72 (1H, dd, J=2.9, 9.2Hz), 8.47 (1H, dd, J=5.5, 9.2 Hz), 10.70 (1H, s).

(2) To a solution of ethyl6-fluoro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(3.21 g, 10 mmol), 1-butanol (1.4 ml, 15 mmol) and tributylphosphine(5.0 ml, 20 mmol) in tetrahydrofuran (30 ml) was added1,1′-azodicarbonylpiperidine (5.05 g, 20 mmol) and the mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography to give ethyl4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(3.55 g, 94.2%) as an oil.

¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.01. (3H, t, J=7.4 Hz), 1.44 (3H, t,J=7.1 Hz), 1.48–1.59 (2H, m), 1.73–1.89 (2H, m), 3.94 (2H, t, J=6.5 Hz),4.07 (2H, bs), 4.44 (2H, q, J=7.1 Hz), 7.21–7.31 (1H, m), 7.38(1H, dd,J=2.5, 9.1 Hz), 8.45 (1H, dd, J=5.6, 8.8 Hz).

(3) To a solution of ethyl4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(3.40 g, 9 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) wasadded sodium hydroxide (1.08 g, 27 mmol). The obtained mixture wasrefluxed under heating for 12 h. The reaction mixture was poured intowater and acidified with 1N hydrochloric acid and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in tetrahydrofuran (20 ml) and oxalyl chloride (0.9 ml,10.8 mmol) and N,N-dimethylformamide (2 drops) were added thereto. Themixture was stirred at room temperature for 1 h. The reaction mixturewas concentrated under reduced pressure, and the residue was dissolvedin tetrahydrofuran (20 ml). The obtained solution was added dropwise toa suspension of sodium tetrahydroborate (1.13 g, 30 mmol) in1,2-dimethoxyethane (20 ml) at 0° C. The obtained mixture was stirred at0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyand the component eluted earlier was concentrated to give4-butoxy-6-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (1.72g, 57.1%) as crystals.

Melting point 143–143.5° C. Elemental analysis for C₁₉H₂₆NO₃FCalculated: C, 68.04; H, 7.81; N, 4.18. Found: C, 67.85; H, 7.72; N,4.20. ¹H-NMR(CDCl₃) δ: 96 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.50–1.68(2H, m), 1.79–1.93 (2H, m), 2.46 (1H, bs), 3.88 (2H, t, J=6.6 Hz), 4.17(2H, bs), 4.87 (2H, bs), 7.08–7.18 (1H, m), 7.24–7.30 (1H, m), 8.28–8.37(1H, m).

The component eluted later was concentrated to give4-butoxy-6-ethoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (0.51g, 15.7%) as crystals.

Melting point 92.5–93.0° C. Elemental analysis for C₂₁H₃₁NO₄ Calculated:C, 69.78; H, 8.64; N, 3.87. Found: C, 69.84; H, 8.65; N, 3.68.1H-NMR(CDCl₃) δ: 0.95 (9H, s), 1.03 (3H, t, J=7.3 Hz), 1.48 (3H, t,J=7.0 Hz), 1.54–1.66 (2H, m), 1.79–1.89 (2H, m), 2.77 (1H, bs), 3.89(2H, t, J=6.4 Hz), 4.13 (2H, q, J=7.0 Hz), 4.18 (2H, bs), 4.85 (2H, bs),6.93–6.98 (2H, m), 8.17–8.22 (1H, m).

(4) To a solution of4-butoxy-6-ethoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (0.43g, 1.2 mmol) in tetrahydrofuran (10 ml) and toluene (10 ml) was addedthionyl chloride (0.18 ml, 2.4 mmol). The obtained mixture was refluxedunder heating for 2 h. The reaction mixture was poured into saturatedaqueous sodium hydrogencarbonate solution and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give4-butoxy-6-ethoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (0.41g, 91.1%) as an oil.

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.04 (3H, t, J=7.3 Hz), 1.48 (3H, t,J=7.0 Hz), 1.55–1.70 (2H, m), 1.81–1.91 (2H, m), 3.95 (2H, t, J=6.5 Hz),4.10 (2H, bs), 4.15 (2H, q, J=7.0 Hz), 4.87 (2H, bs), 7.05–7.30 (2H, m),8.34 (1H, d, J=9.4 Hz).

(5) A solution of4-butoxy-6-ethoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (0.38g, 1 mmol) and potassium phthalimide (0.28 g, 1.5 mmol) inN,N-dimethylformamide (10 ml) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give2-{(4-butoxy-6-ethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(0.48 g, 98.0%) as an amorphous.

Elemental analysis for C₂₉H₃₄N₂O₅ Calculated: C, 71.00; H, 6.99; N,5.71. Found: C, 71.41; H, 7.15; N, 5.64. ¹H-NMR(CDCl₃) δ: 1.00 (9H, s),1.01 (3H, t, J=7.3 Hz), 1.48 (3H, t, J=7.0 Hz), 1.50–1.61 (2H, m),1.81–1.94 (2H, m), 3.99 (2H, bs), 4.02 (2H, t, J=6.8 Hz), 4.15 (2H, q,J=7.0 Hz), 5.07 (2H, s), 7.02–7.10 (2H, m), 7.69–7.80 (1H, m), 8.31 (1H,d, J=8.8 Hz).

(6) To a solution of2-{(4-butoxy-6-ethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(0.43 g, 1.2 mmol) in ethanol (20 ml) was added hydrazine monohydrate(0.13 ml, 2.7 mmol). The obtained mixture was refluxed under heating for2 h. The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (20 ml) and di-t-butyl dicarbonate (0.31 g, 1.4 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl(4-butoxy-6-ethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.36 g, 87.8%) as crystals.

Melting point 138–139° C. Elemental analysis for C₂₆H₄₀N₂O₅ Calculated:C, 67.80; H, 8.75; N, 6.08. Found: C, 67.76; H, 8.91; N, 5.87.¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.03 (3H, t, J=7.0 Hz), 1.45 (9H, s),1.49 (3H, t, J=7.0 Hz), 1.52–1.64 (2H, m), 1.79–1.91 (2H, m), 3.96 (2H,t, J=6.4 Hz), 4.10 (2H, bs), 4.15 (2H, q, J=7.0 Hz), 4.55 (2H, d, J=5.6Hz), 4.67 (1H, bs), 7.02–7.08 (2H, m), 8.29–8.34 (1H, m).

(7) To a solution oftert-butyl(4-butoxy-6-ethoxy-2neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.28 g, 0.6 mmol) in ethyl acetate (5 ml) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 ml), and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diisopropyl ether to give3-(aminomethyl)-4-butoxy-6-ethoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride (0.23 g, 95.8%) as crystals.

Melting point 195.5–201° C. Elemental analysis for C₂₁H₃₃N₂O₃Cl ¼H₂OCalculated: C, 62.83; H, 8.41; N, 6.98. Found: C, 62.79; H, 8.52; N,6.72. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.41 (3H,t, J=7.0 Hz), 1.51–1.63 (2H, m), 1.77–1.91 (2H, m), 3.93 (2H, t, J=6.4Hz), 4.09 (2H, bs), 4.20 (2H, q, J=7.0 Hz), 4.22 (2H, s), 7.07 (1H, d,J=2.2 Hz), 7.18 (1H, dd, J=2.2, 8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.56(3H, bs).

Example 23-(Aminomethyl)-4-butoxy-7-fluoro-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) To a solution of ethyl7-fluoro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(5.12 g, 31.9%) (from Example 1(1), 3.21 g, 10 mmol), 1-butanol (1.4 ml,15 mmol) and tributylphosphine (5.0 ml, 20 mmol) in tetrahydrofuran (30ml) was added 1,1′-(azodicarbonyl)dipiperidine (5.05. g, 20 mmol) andthe mixture was stirred at room temperature for 3 h. The reactionmixture was concentrated, under reduced pressure and the residue waspurified by silica gel column chromatography to give ethyl4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(3.55 g, 94.2%) as an oil.

¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.01 (3H, t, J=7.1 Hz), 1.44 (3H, t,J=7.1 Hz), 1.51–1.63 (2H, m), 1.73–1.87 (2H, m), 3.95 (2H, t, J=6.4 Hz),4.11 (2H, bs), 4.43 (2H, q, J=7.1 Hz), 7.40–7.50 (1H, m), 7.79 (1H, dd,J=5.2, 8.8 Hz), 8.09 (1H, dd, J=2.8, 9.4 Hz).

(2) To a solution of4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(3.40 g, 9 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) wasadded sodium hydroxide (1.08 g, 27 mmol). The obtained mixture wasrefluxed under heating for 3 h. The reaction mixture was pouted intowater, and, after making the mixture acidic with 1N hydrochloric acid,extracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (3.04 g, 96.8%) as crystals.

Melting point 184–185° C. Elemental analysis for C₁₉H₂₄NO₄F Calculated:C, 65.31; H, 6.92; N, 4.01. Found: C, 65.49; H, 7.11; N, 3.77.¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 0.99 (3H, t, J=7.5 Hz), 1.45–1.64 (2H,m), 1.77–1.91 (2H, m), 4.03 (2H, t, J=6.6 Hz), 4.30 (2H, bs), 5.67 (1H,bs), 7.42–7.52 (1H, m), 7.80 (1H, dd, J=5.2, 8.8 Hz), 8.09 (1H, dd,J=2.6, 9.2 Hz).

(3)4-Butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (2.97 g, 8.5 mmol) was dissolved in tetrahydrofuran (30 ml) andoxalyl chloride (0.9 ml, 10.2 mmol) and N,N-dimethylformamide (2 drops)were added thereto. The mixture was stirred at room temperature for 1 h.The reaction mixture was concentrated under reduced pressure and theresidue was dissolved in tetrahydrofuran (20 ml). The obtained solutionwas added dropwise to sodium tetrahydroborate (1.13 g, 30 mmol) indimethoxyethane (20 ml) at 0° C. The obtained mixture was stirred at 0°C. for 1 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give4-butoxy-7-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (2.52g, 88.4%) as crystals.

Melting point 149–150° C. Elemental analysis for C₁₉H₂₆NO₃F Calculated:C, 68.04; H, 7.81; N, 4.18. Found: C, 67.80; H, 8.00; N, 4.19.¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 1.04 (3H, t, J=7.1 Hz), 1.50–1.69 (2H,m), 1.71–1.94 (2H, m), 2.93 (1H, bs), 3.91 (2H, t, J=6.6 Hz), 4.21 (2H,bs), 4.87 (2H, bs), 7.27–7.36 (1H, m), 7.65 (1H, dd, J=5.0, 8.8 Hz),7.86 (1H, dd, J=2.4, 9.2 Hz).

(4) To a solution of4-butoxy-7-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone(2.35g, 7 mmol) in tetrahydrofuran (10 ml) and toluene (10 ml) was addedthionyl chloride (1.0 ml, 14 mmol) and the obtained mixture was refluxedunder heating for 2 h. The reaction mixture was poured into saturatedaqueous sodium hydrogencarbonate solution and extracted with ethylacetate. The extract was washed with brine dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give4-butoxy-7-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (2.04g, 82.6%) as an oil.

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.3 Hz), 1.51–1.69 (2H,m), 1.81–1.91 (2H, m), 3.94 (2H, t, J=6.4 Hz), 4.20 (2H, bs), 4.88 (2H,bs), 7.38–7.48 (1H, m), 7.75 (1H, dd, J=5.0, 8.8 Hz), 8.09 (1H, dd,J=2.6, 9.0 Hz).

(5) A solution of4-butoxy-7-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.95g, 5.5 mmol) and potassium phthalimide (1.54 g, 8.3 mmol) inN,N-dimethylformamide (20 ml) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give2-{(4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(2.46 g, 96.5%) as crystals.

Melting point 155–156° C. Elemental analysis for C₂₇H₂₉N₂O₄F Calculated:C, 69.81; H, 6.29; N, 6.03. Found: C, 69.84; H, 6.17; N, 5.88.¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.3 Hz), 1.01 (9H, s), 1.45–1.62 (2H,m), 1.81–1.95 (2H, m), 4.02 (2H, t, J=6.7 Hz), 4.13 (2H, bs), 5.07 (2H,bs), 7.36–7.45 (1H, m), 7.69–7.83 (5H, m), 8.05 (1H, dd, J=2.6, 9.4 Hz).

(6) To a suspension of2-{(4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(2.32 g, 5 mmol) in ethanol (20 ml) was added hydrazine monohydrate(0.73 ml, 15 mmol). The obtained mixture was refluxed under heating for2 h. The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (20 ml) and di-t-butyl dicarbonate (1.64 g, 7.5 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-diisopropyl ether togivetert-butyl(4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(1.93 g, 88.9%) as crystals.

Melting point 149–150° C. Elemental analysis for C₂₄H₃₅N₂O₄F Calculated:C, 66.34; H, 8.12; N, 6.45. Found: C, 66.33; H, 8.14; N, 6.33.¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.03 (3H, t, J=7.4 Hz), 1.45 (9H, s),1.52–1.67 (2H, m), 1.79–1.93 (2H, m), 3.86 (2H, t, J=6.4 Hz), 4.13 (2H,bs), 4.57 (2H, d, J=5.6 Hz), 4.68 (1H, bs), 7.36–7.45 (1H, m), 7.70 (1H,dd, J=5.1, 8.7 Hz), 8.05 (1H, dd, J=2.7, 9.3 Hz).

(7) To a solution oftert-butyl(4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(1.74 g, 4 mmol) in ethyl acetate (5 ml) was added a solution of 4Nhydrogen chloride in ethyl acetate(5 ml), and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure and the precipitated crystals were,recrystallized from methanol-diisopropyl ether to give3-(aminomethyl)-4butoxy-7-fluoro-2-neopentyl-1(2H)-isoquinolinonehydrochloride (1.42 g, 95.9%) as crystals.

Melting point 198–199° C. Elemental analysis for C₁₉H₂₈N₂O₂ClF ½H₂OCalculated: C, 60.07; H, 7.69; N, 7.37. Found: C, 60.33; H, 7.57; N,7.42. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 0.99 (3H, t, J=7.4 Hz), 1.45–1.64(2H, m), 1.78–1.92 (2H, m), 3.94 (2H, t, J=6.4 Hz), 4.12 (2H, bs), 4.25(2H, bs), 7.70–7.80 (1H, m), 7.87 (1H, dd, J=5.4, 9.0 Hz), 7.95. (1H,dd, J=2.5, 9.5 Hz), 8.60 (3H, bs).

Example 33-(Aminomethyl)-4-butoxy-6-fluoro-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) To a solution of4-butoxy-6-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (fromExample 1(3), 1.68 g, 5 mmol) in tetrahydrofuran (10 ml) and toluene (10ml) was added thionylchloride (0.73 ml, 10 mmol), and the resultingmixture was refluxed under heating for 2 h. The reaction mixture waspoured into saturated aqueous sodium hydrogencarbonate solution andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reduced pressureto give4-butoxy-6-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.62g, 92.0%) as an oil.

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.04 (3H, t, J=7.4 Hz), 1.51–1.69 (2H,m), 1.81–1.95 (2H, m), 3.94 (2H, t, J=6.6 Hz), 4.17 (2H, bs), 4.87 (2H,bs), 7.12–7.30 (1H, m), 7.35 (1H, dd, J=2.6, 9.6 Hz), 8.09 (1H, dd,J=5.8, 9.0 Hz).

(2) A solution of4-butoxy-6-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.59g, 4.5 mmol) and potassium phthalimide (1.26 g, 6.8 mmol) inN,N-dimethylformamide (20 ml) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give2-{(4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(1.81 g, 86.6%) as crystals.

Melting point 162–164° C. Elemental analysis for C₂₇H₂₉N₂O₄F Calculated:C, 69.81; H,6.29; N, 6.03. Found: C, 69.47; H, 6.10; N, 6.02.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.01 (3H, t, J=7.3 Hz), 1.48–1.62 (2H,m), 1.81–1.95 (2H, m), 4.01 (2H, t, J=6.8 Hz), 4.04 (2H, bs), 5.07 (2H,bs), 7.13–7.23 (1H, m), 7.34 (1H, dd, J=2.4, 9.8 Hz), 7.70–7.86 (4H, m),8.42 (1H, dd, J=5.6, 8.8 Hz).

(3) To a suspension of2-{(4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(1.71 g, 3.7 mmol) in ethanol (20 ml) was added hydrazine monohydrate(0.54 ml, 11.1 mmol). The resulting mixture was refluxed under heatingfor 2 h. The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (20 ml) and di-t-butyl dicarbonate (1.22 g, 5.6 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingcrystals were recrystallized from ethyl acetate-n-hexane to givetert-butyl(4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(1.35 g, 83.9%) as crystals.

Melting point 168–169° C. Elemental analysis for C₂₄H₃₅N₂O₄F Calculated:C, 66.34; H, 18.12; N, 6.45. Found: C, 66.18; H, 8.26; N, 6.34.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.04 (3H, t, J=7.0 Hz), 1.45 (9H, s),1.52–1.67 (2H, m), 1.79–1.93 (2H, m), 3.85. (2H, t, J=6.4 Hz), 4.11 (2H,bs), 4.56 (2H, d, J=5.2 Hz), 4.68 (1H, bs), 7.14–7.24 (1H, m), 7.30 (1H,dd, J=2.6, 10.0 Hz), 8.42 (1H, dd, J=5.4, 8.8 Hz).

(4) To a solution oftert-butyl(4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(1.22 g, 2.8 mmol) in ethyl acetate (5 ml) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 ml) and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diisopropyl ether to give3-(aminomethyl)-4-butoxy-6-fluoro-2-neopentyl-1(2H)-isoquinolinehydrochloride (1.01 g, 98.1%) as crystals.

Melting point 195.5–201° C. Elemental analysis for C₁₉H₂₈N₂O₂ClF ¼H₂OCalculated: C, 62.83; H, 8.41; N, 6.98. Found: C, 62.79; H, 8.52; N,6.72. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.41 (3H,t, J=7.0 Hz), 1.51–1.63 (2H, m), 1.77–1.91 (2H, m), 3.93 (2H, t, J=6.4Hz), 4.09 (2H, bs), 4.20(2H, q, J=7.0 Hz), 4.22 (2H, s), 7.07 (1H, d,J=2.2 Hz), 7.18 (1H, dd, J=2.2, 8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.56(3H, bs).

Example 43-(Aminomethyl)-6-chloro-4-methoxy-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) To a solution of 4-chlorophthalic anhydride (9.13 g, 50 mmol) intetrahydrofuran (50 ml) was added 28% sodium methoxide-methanol solution(11.6 ml, 60 mmol), and the mixture was stirred at room temperature for30 min. The reaction mixture was poured into water, and, after makingthe mixture acidic with 1N hydrochloric acid, extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in tetrahydrofuran (100 ml) and oxalyl chloride (5.2 ml,60 mmol) and N,N-dimethylformamide (3 drops) were added thereto. Themixture was stirred at room temperature for 30 min. The reaction mixturewas concentrated under reduced pressure, and the residue was dissolvedin N,N-dimethylacetamide (100 ml). To the obtained solution was addedethyl sarcosinate hydrochloride (9.22 g, 60 mmol). The obtained mixturewas stirred at room temperature for 2 h. The reaction mixture was pouredinto 1N hydrochloric acid and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved inethanol (100 ml) and 20% sodium ethoxide ethanol solution (27.2 g, 80mmol) was added. The mixture was stirred at room temperature for 1 h.The reaction mixture was poured into 1N hydrochloric acid (100 ml) andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyand the component eluted earlier was concentrated to give ethyl7-chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(2.24 g, 20.9%) as crystals.

Melting point 109–110° C. Elemental analysis for C₁₃H₁₂NO₄Cl Calculated:C, 55.43; H, 4.29; N, 4.97. Found: C, 55.54; H, 4.22; N, 5.12.¹H-NMR(CDCl₃) δ: 1.46 (3H, t, J=7 Hz), 3.68 (3H, s), 4.50 (2H, q, J=7.0Hz), 7.70 (1H, dd, J=2.0, 8.6 Hz), 8.09 (1H, d, J=8.6 Hz), 8.43 (1H, d,J=2.0 Hz), 11.25 (1H, s).

The component eluted later was concentrated to give ethyl6-chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(2.82 g, 26.4%) as crystals.

Melting point 110–111° C. Elemental analysis for C₁₃H₁₂NO₄Cl Calculated:C, 55.43; H, 4.29; N, 4.97. Found: C, 55.49; H, 4.30; N, 5.11.¹H-NMR(CDCl₃) δ: 1.46 (3H, t, J=7.0 Hz), 3.68 (3H, s), 4.50 (2H, q,J=7.0 Hz), 7.63 (1H, dd, J=1.9, 8.7 Hz), 8.17 (1H, d, J=1.9 Hz), 8.38(1H, d, J=8.7 Hz), 11.16 (1H, s).

(2) A suspension of ethyl6-chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(1.41 g, 5 mmol), methyl iodide (0.47 ml, 7.5 mmol) and potassiumcarbonate (1.04 g, 7.5 mmol) in N,N-dimethylformamide (10 ml) wasstirred at room temperature for 4 h. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give ethyl6-chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(1.11 g, 75.5%) as crystals.

Melting point 122–123° C. Elemental analysis for C₁₄H₁₄NO₄Cl Calculated:C, 56.86; H, 4.77; N, 4.74. Found: C, 56.85; H, 4.76; N, 4.57.¹H-NMR(CDCl₃) δ: 1.45 (3H, t, J=7.2 Hz), 3.52 (3H, s), 3.89 (3H, s),4.49 (2H, q, J=7.2 Hz), 7.51 (1H, dd, J=2.2, 8.8 Hz), 7.74 (1H, d, J=2.2Hz), 8.38 (1H, d, J=8.8 Hz).

(3) To a solution of ethyl6-chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(1.03 g, 3.5 mmol) in tetrahydrofuran (10 ml) and ethanol (10 ml) wasadded 1N sodium hydroxide (5 ml). The obtained mixture was refluxedunder stirring at 50° C. for 3 h. The reaction mixture was poured intowater, acidified with 1N hydrochloric acid and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate diethyl ether to give6-chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (0.72 g, 77.4%) as crystals.

Melting point 216–217° C. Elemental analysis for C₁₂H₁₀NO₄Cl Calculated:C, 53.85; H, 3.77; N, 5.23. Found: C, 53.78; H, 3.74; N, 5.03.¹H-NMR(CDCl₃) δ: 3.58 (3H, s), 3.91 (3H, s), 4.78 (1H, bs), 7.49 (1H,dd, J=2.0, 8.6 Hz), 7.75 (1H, d, J=2.0 Hz), 8.36 (1H, d, J=8.6 Hz).

(4)6-Chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (0.67 g, 2.5 mmol) was dissolved in tetrahydrofuran (10 ml) andoxalyl chloride (0.26 ml, 3 mmol) and N,N-dimethylformamide (2 drops)were added thereto. The mixture was stirred at room temperature for 1 h.The reaction mixture was concentrated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (10 ml). The obtained solutionwas added dropwise to a suspension of sodium tetrahydroborate (0.33 g,8.8 mmol) in 1,2-dimethoxyethane (20 ml) at 0° C. The obtained mixturewas stirred at 0° C. for 1 h, and the reaction mixture was poured into1N hydrochloric acid and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained crystals wererecrystallized from ethyl acetate-diisopropyl ether to give6-chloro-3-hydroxymethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.42g, 66.7%) as crystals.

Melting point 195–196° C. Elemental analysis for C₁₂H₁₂NO₃Cl Calculated:C, 56.81; H, 4.77; N, 5.52. Found: C, 56.69; H, 4.88; N, 5.44.¹H-NMR(CDCl₃) δ: 2.70 (1H, bs), 3.71 (3H, s), 3.82 (3H, s), 4.82 (2H,s), 7.40 (1H, dd, J=2.0, 8.6 Hz), 7.61 (1H, d, J=2.0 Hz), 8.26 (1H, d,J=8.6 Hz).

(5) To a solution of6-chloro-3-hydroxymethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.76g, 3 mmol) in tetrahydrofuran (20 ml) was added thionyl chloride (0.26ml, 3.6 mmol). The obtained mixture was refluxed under heating for 2 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution, extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-chloro-3-chloromethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.73 g,90.1%) as crystals.

¹H-NMR(CDCl₃) δ: 3.73 (3H, s), 3.93 (3H, s), 4.80 (2H, s), 7.49 (1H, dd,J=2.0, 8.6 Hz), 7.74 (1H, d, J=2.0 Hz), 8.38 (1H, d, J=8.6 Hz).

(6) A solution of6-chloro-3-chloromethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.81 g,3 mmol) and potassium phthalimide (0.83 g, 4.5 mmol) inN,N-dimethylformamide (20 ml) was stirred at room temperature for 4 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give2-{(6-chloro-4methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(0.59 g, 51.8%) as crystals.

Melting point 248–249° C. Elemental analysis for C₂₀H₁₅N₂O₄ClCalculated: C, 62.75; H, 3.95; N, 7.32. Found: C, 62.73; H, 3.94; N,7.32. ¹H-NMR(CDCl₃) δ: 3.61 (3H, s), 3.96 (3H, s), 5.07 (2H, s), 7.45(1H, dd, J=2.0, 8.6 Hz), 7.73–7.88 (5H, m), 8.36 (1H, d, J=8.6 Hz).

(7) To a solution of2-{(6-chloro-4-methoxy-2-methyl-1oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(0.38 g, 1 mmol) in ethanol (10 ml) and tetrahydrofuran (10 ml) wasadded hydrazine monohydrate (0.14 ml, 3 mmol). The obtained mixture wasrefluxed under heating for 2 h. The reaction mixture was poured intosaturated aqueous sodium hydrogencarbonate solution and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. To theresidue was added a solution of 4N hydrogen chloride in ethyl acetate (2ml), and the precipitated crystals were recrystallized frommethanol-diethyl ether to give3-(aminomethyl)-6-chloro-4-methoxy-2-methyl-1(2H)-isoquinolinonehydrochloride (0.08 g, 28.6%) as crystals.

Melting point 236–237° C. Elemental analysis for C₁₂H₁₄N₂O₂Cl₂Calculated: C, 49.84; H, 4.88; N, 9.69. Found: C, 49.67; H, 4.71; N,9.48. ¹H-NMR(DMSO-d₆) δ: 3.61 (3H, s), 3.85 (3H, s), 4.24 (2H, s), 7.66(1H, dd, J=2.0, 8.6 Hz), 7.81 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=8.6 Hz),8.75 (3H, bs).

Example 53-(Aminomethyl)-7-chloro-4-methoxy-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl7-chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 4 (2))

Melting point 114–115° C. Elemental analysis for C₁₄H₁₄NO₄Cl Calculated:C, 56.86; H, 4.77; N, 4.74. Found: C, 56.77; H, 4.74; N, 4.64.¹H-NMR(CDCl₃) δ: 1.45 (3H, t, J=7.1 Hz), 3.53 (3H, s), 3.89 (3H, s),4.49 (2H, q, J=7.1 Hz), 7.67 (1H, dd, J=2.0, 8.6 Hz), 7.74 (1H, d, J=8.0Hz), 8.38 (1H, d, J=2.0 Hz).

(2)7-Chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 163–164° C. Elemental analysis for C₁₂H₁₀NO₄Cl Calculated:C, 53.85; H, 3.77; N, 5.23. Found: C, 53.78; H, 3.74; N, 5.03.¹H-NMR(CDCl₃) δ: 3.60 (3H, s), 3.91 (3H, s), 7.66 (1H, dd, J=2.2, 8.8Hz), 7.76 (1H, d, J=2.2 Hz), 8.40 (1H, d, J=2.2 Hz).

(3) 7-Chloro-3-hydroxymethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 151–152° C. Elemental analysis for C₁₂H₁₂NO₃Cl ¼H₂OCalculated: C, 55.83; H, 4.88; N, 5.43. Found: C, 55.88; H, 4.84; N,5.55. ¹H-NMR(CDCl₃) δ: 2.57 (1H, bs), 3.73 (3H, s), 3.84 (3H, s), 4.83(2H, s), 7.59 (1H, dd, J=2.0, 8.6 Hz), 7.66 (1H, d, J=8.6 Hz), 8.33 (1H,d, J=2.0 Hz).

(4) 7-Chloro-3-chloromethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.74 (3H, s), 3.93 (3H, s), 4.81 (2H, s), 7.66 (1H, dd,J=2.2, 8.6 Hz), 7.66 (1H, d, J=8.6 Hz), 8.33 (1H, d, J=2.2 Hz).

(5)2-{(7-Chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 262–263° C. Elemental analysis for C₂₀H₁₅N₂O₄ClCalculated: C, 62.75; H, 3.95; N, 7.32. Found: C, 62.41; H, 3.91; N,7.20. ¹H-NMR(CDCl₃) δ: 3.56 (3H, s), 3.82 (3H, s), 5.02 (2H, s),7.81–7.86 (6H, m), 8.18 (1H, s).

(6) 3-(Aminomethyl)-7-chloro-4-methoxy-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 4 (7))

Melting point 225–226° C. Elemental analysis for C₁₂H₁₄N₂O₂Cl₂Calculated: C, 49.84; H, 4.88; N, 9.69. Found: C, 49.82; H, 4.88; N,10.12. ¹H-NMR(DMSO-d₆) δ: 3.62 (3H, s), 3.84 (3H, s), 4.23 (2H, d, J=4.4Hz), 7.83–7.88 (2H, m), 8.22 (1H, d, J=0.8 Hz), 8.72 (3H, bs).

Example 63-(Aminomethyl)-6-chloro-4-isopropoxy-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-4-isopropoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 4 (2))

Melting point 66–67° C. Elemental analysis for C₁₆H₁₈NO₄Cl Calculated:C, 59.35; H, 5.60; N, 4.33. Found: C, 59.22; H, 5.56; N, 4.33.¹H-NMR(CDCl₃) δ: 1.32 (6H, d, J=6.2 Hz), 1.45 (3H, t, J=7.2 Hz), 3.52(3H, s), 4.28–4.40 (1H, m) 4.47 (2H, q, J=7.2 Hz), 7.50 (1H, dd, J=2.9,8.6 Hz), 7.75 (1H, d, J=2.0 Hz), 8.37 (1H, d, J=8.6 Hz).

(2)6-Chloro-4-isopropoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 229–230° C. Elemental analysis for C₁₄H₁₄NO₄Cl Calculated:C, 56.86; H, 4.77; N, 4.74. Found: C, 56.86; H, 4.79; N, 4.48.¹H-NMR(CDCl₃) δ: 1.34 (6H, d, J=6.2 Hz), 3.60 (3H, s), 4.34–4.46 (1H,m), 7.48 (1H, dd, J=2.2, 8.4 Hz), 7.77 (1H, d, J=2.2 Hz), 8.36 (1H, d,J=8.4 Hz).

(3) 6-Chloro-3-hydroxymethyl-4-isopropoxy-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 146–147° C. Elemental analysis for C₁₄H₁₆NO₃Cl Calculated:C, 59.68; H, 5.72; N, 4.97. Found: C, 59.43; H, 5.70; N, 5.06.¹H-NMR(CDCl₃) δ: 1.35 (6H, d, J=6.2 Hz), 2.34 (1H, bs), 3.74 (3H, s),4.12–4.24 (1H, m), 4.83 (2H, d, J=4.8 Hz), 7.41 (1H, d, J=8.6 Hz), 7.61(1H, s), 8.30 (1H, d, J=8.6 Hz).

(4)2-{(6-Chloro-4-isopropoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 175–176° C. Elemental analysis for C₂₂H₁₉N₂O₄Cl ½H₂OCalculated: C, 62.93; H, 4.80; N, 6.67. Found: C, 62.78; H, 4.65; N,6.41. ¹H-NMR(CDCl₃) δ: 1.41 (6H, d, J=5.8 Hz), 3.60 (3H, s), 4.27–4.39(1H, m), 5.08 (2H, s), 7.43 (1H, dd, J=2.0, 8.6 Hz), 7.68–7.90 (5H, m),8.34 (1H, d, J=8.6 Hz).

(5) 3-(Aminomethyl)-6-chloro-4-isopropoxy-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 4 (7))

Melting point 218–220° C. Elemental analysis for C₁₄H₁₈N₂O₂Cl₂ ½H₂OCalculated: C, 52.27; H, 5.80; N, 8.71. Found: C, 52.37; H, 5.84; N,8.70. ¹H-NMR(DMSO-d₆) δ: 1.34 (6H, d, J=5.8 Hz), 3.61 (3H, s), 4.21–4.30(3H, m), 7.65 (1H, dd, J=1.8, 8.6 Hz), 7.72 (1H, d, J=1.8 Hz), 8.28 (1H,d, J=8.6 Hz), 8.73 (3H, bs).

Example 73-(Aminomethyl)-4-butoxy-6-chloro-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl4-butoxy-6-chloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 4 (2))

¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.3 Hz), 1.45 (3H, t, J=7.2 Hz),1.51–1.63 (2H, m), 1.73–1.87 (2H, m), 3.52 (3H, s), 3.97 (2H, t, J=6.4Hz), 4.48 (2H, q, J=7.2 Hz), 7.50 (1H, dd, J=2.0, 8.6 Hz), 7.71 (1H, d,J=2.0 Hz), 8.38 (1H, d, J=8.6 Hz).

(2)4-Butoxy-6-chloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 160–161° C. Elemental analysis for C₁₅H₁₆NO₄Cl Calculated:C, 58.16; H, 5.21; N, 4.52. Found: C, 58.34; H, 5.42; N, 4.58.¹H-NMR(CDCl₃) δ: 0.95 (3H, t, J=7.2 Hz), 1.39–1.57 (2H, m), 1.67–1.80(2H, m), 3.43 (3H, s), 3.95 (2H, t, J=6.4 Hz), 7.65 (1H, dd, J=2.0, 8.6Hz), 7.73 (1H, d, J=2.0 Hz), 8.26 (1H, d, J=8.6 Hz).

(3) 4-Butoxy-6-chloro-3-hydroxymethyl-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 110–111° C. Elemental analysis for C₁₅H₁₈NO₃Cl Calculated:C, 60.91; H, 6.18; N, 4.74. Found: C, 61.06; H, 6.09; N, 4.92.¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J 7.3 Hz), 1.50–1.65 (2H, m), 1.76–1.90(2H, m), 2.82 (1H, bs), 3.69 (3H, s), 3.82 (2H, t, J=6.4 Hz), 4.79 (2H,d, J=5.4 Hz), 7.39 (1H, dd, J=2.1, 8.5 Hz), 7.54 (1H, d, J=2.1 Hz), 8.24(1H, d, J=8.5 Hz).

(4) 4-Butoxy-6-chloro-3-chloromethyl-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.05 (3H, t, J=7.3 Hz), 1.56–1.71 (2H, m), 1.83–1.97(2H, m), 3.73 (3H, s), 3.99 (2H, t, J=6.4 Hz), 4.80 (2H, s), 7.46 (1H,dd, J=2.2, 8.6 Hz), 7.71 (1H, d, J=2.2 Hz), 8.38 (1H, d, J=8.6 Hz).

(5)2-{(4-Butoxy-6-chloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6)).

Melting point 200–201° C. Elemental analysis for C₂₃H₂₁N₂O₄ClCalculated: C, 65.02; H, 4.98; N, 6.59. Found: C, 64.85; H, 5.07; N,6.60. ¹H-NMR(DMSO-d₆) δ: 0.93 (3H, t, J=7.4 Hz), 1.40–1.51 (2H, m),1.70–1.81 (2H, m), 3.52 (3H, s), 3.93 (2H, t, J=6.6 Hz), 5.03 (2H, s),7.59 (1H, dd, J=2.0, 8.4 Hz), 7.67 (1H, d, J=2.0 Hz), 7.87 (4H, s), 8.25(1H, d, J=8.4 Hz).

(6) 3-(Aminomethyl)-4-butoxy-6-chloro-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 4 (7))

Melting point 222–223° C. Elemental analysis for C₁₅H₂₀N₂O₂Cl₂ ½H₂OCalculated: C, 60.91; H, 6.13; N, 4.74. Found: C, 61.06; H, 6.09; N,4.92. ¹H-NMR(DMSO-d₆) δ: 1.00 (3H, t, J=7.3 Hz), 1.46–1.64 (2H, m),1.77–1.99 (2H, m), 3.61 (3H, s), 3.91 (2H, t, J=6.4 Hz), 4.23 (2H, bs),7.65 (1H, dd, J=2.0, 8.6 Hz), 7.72 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=8.6Hz), 8.74 (3H, bs).

Example 83-(Aminomethyl)-4-benzyloxy-6-chloro-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl4-benzyloxy-6-chloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 4 (2))

Melting point 114–115° C. Elemental analysis for C₂₀H₁₈NO₄Cl Calculated:C, 64.61; H, 4.88; N, 3.77. Found: C, 64.67; H, 5.04; N, 4.00.¹H-NMR(CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 3.54 (3H, s), 3.97 (2H, q,J=7.2 Hz), 5.03 (2H, s), 7.39–7.54 (6H, m), 7.72 (1H, d, J=1.8 Hz), 8.39(1H, d, J=8.8 Hz).

(2)4-Benzyloxy-6-chloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 226–227° C. Elemental analysis for C₁₈H₁₄NO₄Cl Calculated:C, 62.89; H, 4.10; N, 4.07. Found: C; 62.84; H, 4.16; N, 4.20.¹H-NMR(CDCl₃) δ: 3.61 (3H, s), 5.07 (2H, s), 6.36 (1H, bs), 7.32–7.54(6H, m), 7.72 (1H, d, J=8 Hz), 8.37 (1H, d, J=8.4 Hz).

(3) 4-Benzyloxy-6-chloro-3-hydroxymethyl-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 207–208° C. Elemental analysis for C₁₈H₁₆NO₃Cl Calculated:C, 65.56; H, 4.89; N, 4.25. Found: C, 65.48; H, 4.96; N, 4.39.¹H-NMR(CDCl₃) δ: 1.22 (1H, t, J=5.8 Hz), 3.64 (3H, s), 4.52 (2H, d,J=5.8 Hz), 4.96 ((2H, s), 7.35–7.48 (6H, m), 7.72 (1H, d, J=2.2 Hz),8.36 (1H, d, J=8.4 Hz).

(4) 4-Benzyloxy-6-chloro-3-chloromethyl-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.74 (3H, s), 4.76 (2H, s), 5.04 (2H, s), 7.43–7.52(6H, m), 7.75 (1H, d, J=2.2 Hz), 8.40 (1H, d, J=8.8 Hz).

(5)2-(4-Benzyloxy-6-chloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 243–244° C. Elemental analysis for C₂₆H₁₉N₂O₄Cl H₂OCalculated: C, 65.48; H, 4.44; N, 5.87. Found: C, 65.27; H, 4.22; N,5.99. ¹H-NMR(DMSO-d₆) δ: 3.48 (3H, s), 5.06 (4H, s), 7.38–7.64 (7H, m),7.85 (4H, s), 8.25 (1H, d, J=8.6 Hz).

(6) 3-(Aminomethyl)-4-benzyloxy-6-chloro-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 4 (7))

Melting point 221–223° C. Elemental analysis for C₁₈H₁₈N₂O₂Cl₂ ½H₂OCalculated: C, 52.95; H, 6.22; N, 8.23. Found: C, 53.21; H, 6.25; N,8.28. ¹H-NMR(DMSO-d₆) δ: 3.62 (3H, s), 4.25 (2H, s), 5.02 (2H, s),7.42–7.52 (7H, m), 7.59–7.69 (4H, m),8.29 (1H, d, J=8.4 Hz), 8.72 (3H,bs).

Example 93-(Aminomethyl)-6-chloro-2-methyl-4-(2-quinolinylmethoxy)-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-2-methyl-1-oxo-4-(2-quinolinylmethoxy)-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 4 (2))

Melting point 164–165° C. Elemental analysis for C₂₃H₁₉N₂O₄ClCalculated: C, 65.33; H, 4.53; N, 6.62. Found: C, 65.29; H, 4.52; N,6.33. ¹H-NMR(CDCl₃) δ: 1.31 (3H, t, J=7.1 Hz), 3.56 (3H, s), 4.39 (2H,q, J=7.1 Hz), 5.33 (2H, s), 7.52 (1H, dd, J=1.9, 8.6 Hz), 7.55–7.63 (1H,m), 7.72–7.82 (2H, m), 7.88 (1H, d, J=8.4 Hz), 7.93 (1H, d, J=1.9 Hz),8.11 (1H, d, J=8.6 Hz), 8.29 (1H, d, J=8.4 Hz), 8.41 (1H, d, J=8.4 Hz).

(2)6-Chloro-2-methyl-1-oxo-4-(2-quinolinylmethoxy)-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 268-268° C. ¹H-NMR(DMSO-d₆) δ: 3.51 (3H, s), 5.29 (2H, s),7.43 (1H, dd, J=2.0, 8.8 Hz), 7.59–7.67 (1H, m), 7.75–7.84 (2H, m), 7.87(1H, d, J=8.6 Hz), 8.00–8.06 (2H, m), 8.19 (1H, d, J=8.6 Hz), 8.46 (1H,d, J=8.8 Hz).

(3)6-Chloro-3-hydroxymethyl-2-methyl-4-(2-quinolinylmethoxy)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 206–207° C. Elemental analysis for C₂₁H₁₇N₂O₃Cl ¼H₂OCalculated: C, 65.46; H, 4.58; N, 7.27. Found: C, 65.40; H, 4.47; N,7.23. ¹H-NMR(CDCl₃) δ: 3.78 (3H, s), 4.80 (2H, s), 5.27 (2H, s), 7.42(1H, dd, J=2.0, 8.6 Hz), 7.57–7.93 (5H, m), 8.12 (1H, d, J=8.8 Hz), 8.30(1H, d, J=8.6 Hz), 8.36 (1H, d, J=8.8 Hz).

(4)6Chloro-3-chloromethyl-2-methyl-4-(2-quinolinylmethoxy)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

H-NMR(CDCl₃) δ: 3.76 (3H, s), 4.89 (2H, s), 5.33 (2H, s), 7.50 (1H, dd,J=2.0, 8.4 Hz), 7.57–7.65 (1H, m), 7.74–7.92 (3H, m), 7.95 (1H, d, J=2.0Hz), 8.16 (1H, d, J=8.4 Hz), 8.31 (1H, d, J=8.4 Hz), 8.41 (1H, d, J=8.4Hz). (5)2-{(6-Chloro-2-methyl-1-oxo-4-(2-quinolinylmethoxy)-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 249–250° C. ¹H-NMR(DMSO-d₆) δ: 3.53 (3H, s), 5.16 (2H, s),5.30 (2H, s), 7.59–7.67 (2H, m), 7.80–7.83 (6H, m), 8.00–8.08 (3H, m),8.27 (1H, d, J=9.0 Hz), 8.46 (1H, d, J=8.4 Hz).

(6)3-(Aminomethyl)-6-chloro-2-methyl-4-(2-quinolinylmethoxy)-1(2H)-isoquinolinonedihydrochloride (synthesized according to the method similar to that inExample 4 (7))

Melting point 236° C. Elemental analysis for C₂₁H₂₀N₃O₂Cl₃ ¼H₂OCalculated: C, 55.16; H, 4.52; N, 9.19. Found: C, 55.29; H, 4.54; N,9.12. ¹H-NMR(DMSO-d₆) δ: 3.65 (3H, s), 4.41 (2H, d, J=4.8 Hz), 5.44 (2H,s), 7.67 (1H, dd, J=2.0, 8.8 Hz), 7.17 (1H, t, J=7.3 Hz), 7.96 (1H, t,J=7.3 Hz), 8.07 (1H, d, J=8.6 Hz), 8.15–8.20 (2H, m), 8.30 (1H, d, J=8.8Hz), 8.33 (1H, d, J=8.4 Hz), 8.75 (1H, d, J=8.4 Hz), 8.87 (3H, bs).

Example 103-(Aminomethyl)-6-chloro-2-methyl-4-(2-phenylethoxy)-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-2-methyl-1-oxo-4-(2-phenylethoxy)-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 1.38 (3H, t, J=7.2 Hz), 3.09 (2H, t, J=6.4 Hz), 3.49(3H, s), 4.17 (2H, t, J=6.4 Hz), 4.33 (2H, q, J=7.2 Hz), 7.24–7.40 (6H,m), 7.44 (1H, dd, J=2.1, 8.5 Hz), 8.33 (1H, d, J=8.5 Hz).

(2)6-Chloro-2-methyl-1-oxo-4-(2-phenylethoxy)-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 168–169° C. Elemental analysis for C₁₉H₁₆NO₄Cl Calculated:C, 63.78; H, 4.51; N 3.91. Found: C, 63.73; H, 4.56; N, 3.86.¹H-NMR(DMSO-d₆) δ: 3.06 (2H, t, J=6.4 Hz), 3.43 (3H, s), 4.16 (2H, t,J=6.4 Hz), 7.19 (1H, dd, J=2.0 Hz), 7.28–7.36 (5H, m), 7.58 (1H, dd,J=2.0, 8.6 Hz), 8.20 (1H, d, J=8.6 Hz).

(3)6-Chloro-3-hydroxymethyl-2-methyl-4-(2-phenylethoxy)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 170–171° C. Elemental analysis for C₁₉H₁₈NO₃Cl Calculated:C, 66.38; H, 5.28; N, 4.07. Found: C, 66.18; H, 5.20; N, 3.93.¹H-NMR(CDCl₃) δ: 2.08 (1H, bs), 3.14 (2H, t, J=6.2 Hz), 3.67 (3H, s),4.08 (2H, t, J=6.2 Hz), 4.59 (2H, d, J=5.8 Hz), 7.26–7.43 (7H, m), 8.27(1H, d, J=8.4 Hz).

(4)6-Chloro-3-chloromethyl-2-methyl-4-(2-phenylethoxy)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.19 (2H, t, J=6.4 Hz), 3.69 (3H, s), 4.20 (2H, t,J=6.4 Hz), 4.58 (2H, s), 7.34–7.42 (6H, m), 7.46 (1H, d, J=2.2 Hz), 8.34(1H, d, J=8.0 Hz).

(5)2-{(6-Chloro-2-methyl-1-oxo-4-(2-phenylethoxy)-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 219–220° C. Elemental analysis for C₂₇H₂₁N₂O₄ClCalculated: C, 68.57; H, 4.48; N, 5.92. Found: C, 68.29; H, 4.54; N,5.97. ¹H-NMR(DMSO-d₆) δ: 3.06 (2H, t, J=6.4 Hz), 3.49 (3H, s), 4.14 (2H,t, J=6.4 Hz), 4.96 (2H, s), 7.19–7.30 (6H, m), 7.52 (1H, dd, J=2.2, 8.6Hz), 7.89 (4H, s), 8.19 (1H, d, J=8.6 Hz).

(6)Tert-butyl(6-chloro-2-methyl-1-oxo-4-(2-phenylethoxy)-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 163–164° C. Elemental analysis for C₂₄H₂₇N₂O₄ClCalculated: C, 65.08; H, 6.14; N, 6.32. Found: C, 65.16; H, 6.32; N,6.15. ¹H-NMR(CDCl₃) δ: 1.47 (9H, s), 3.15 (2H, t, J=6.4 Hz), 3.59 (3H,s), 4.04 (2H, t, J=6.4 Hz), 4.34 (2H, d, J=6.0 Hz), 4.60 (1H, bs),7.27–7.41 (7H, m), 8.29 (1H, d, J=8.8 Hz).

(7)3-(Aminomethyl)-6-chloro-2-methyl-4-(2-phenylethoxy)-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 200–201° C. Elemental analysis for C₁₉H₂₀N₂O₂Cl₂ ¾H₂OCalculated: C, 58.10; H, 5.52; N, 7.13. Found: C, 58.23; H, 5.77; N,7.11. ¹H-NMR(DMSO-d₆) δ: 3.16 (2H, t, J=6.4 Hz), 3.58 (3H, s), 4.11 (2H,t, J=6.4 Hz), 4.25 (2H, d, J=5.6 Hz), 7.21 (1H, d, J=2.0 Hz), 7.29–7.45(5H, m), 7.58 (1H, dd, J=2.0, 8.6 Hz), 8.22 (1H, d, J=8.6 Hz), 8.68 (3H,bs).

Example 113-(Aminomethyl)-6-chloro-2-methyl-4-(1-naphthylmethoxy)-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-2-methyl-4-(1-naphthylmethoxy)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

Melting point 158–159° C. Elemental analysis for C₂₄H₂₀NO₄Cl Calculated:C, 68.33; H, 4.78; N, 3.32. Found: C, 68.25; H, 4.559; N, 3.21.¹H-NMR(CDCl₃) δ: 1.24 (3H, t, J=7.2 Hz), 3.53 (3H, s), 4.19 (2H, q,J=7.2 Hz), 5.50 (2H, s), 7.45–7.63 (5H, m), 7.68 (1H, d, J=2.2 Hz),7.87–7.95 (2H, m), 8.09–8.14 (1H, m), 8.39 (1H, d, J=8.4 Hz).

(2)6-Chloro-2-methyl-4-(1-naphthylmethoxy)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 166–167° C. Elemental analysis for C₂₂H₁₆NO₄Cl Calculated:C, 67.10; H, 4.10; N, 3.56. Found: C, 66.93; H, 3.95; N, 3.49.¹H-NMR(DMSO-d₆) δ: 3.50 (3H, s), 5.49 (2H, s), 7.51–7.68 (6H, m),7.96–8.04 (2H, m), 8.20–8.28 (2H, m).

(3)6-Chloro-3-hydroxymethyl-2-methyl-4-(1-naphthylmethoxy)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 202–203° C. Elemental analysis for C₂₂H₁₈NO₃Cl Calculated:C, 69.57; H, 4.78; N, 3.69. Found: C, 69.18; H, 5.11; N, 3.61.¹H-NMR(DMSO-d₆) δ: 3.64 (3H, s), 4.63 (2H, d, J=5.0 Hz), 5.47 (2H, s),5.59 (1H, t, J=5.0 Hz), 7.50–7.69 (6H, m) 7.96–8.04 (2H, m), 8.21–8.25(2H, m).

(4)6-Chloro-3-chloromethyl-2-methyl-4-(1-naphthylmethoxy)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.72 (3H, s), 4.67 (2H, s), 5.52 (2H, s), 7.45–7.67(6H, m), 7.71 (1H, d, J=1.8 Hz), 7.89–7.97 (2H, m), 8.16 (1H, d, J=8.0Hz), 8.39 (1H, d, J=8.4 Hz).

(5)2-{(6-Chloro-2-methyl-4-(1-naphthylmethoxy)-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 211–212° C. ¹H-NMR(DMSO-d₆) δ: 3.49 (3H, s), 5.09 (2H, s),5.58 (2H, s), 7.45–7.68 (6H, m), 7.84 (4H, s), 7.91–8.01 (2H, m)8.14–8.19 (1H, m), 8.23 (1H, d J=8.8 Hz).

(6)Tert-butyl(6-chloro-2-methyl-4-(1-naphthylmethoxy)-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 205–206° C. Elemental analysis for C₂₇H₂₇N₂O₄ClCalculated: C, 67.71; H, 5.68; N, 5.85. Found: C, 67.50; H, 5.90; N,5.70. ¹H-NMR(CDCl₃) δ: 1.37 (9H, s), 3.14 (1H, bs), 3.45 (3H, s), 4.02(2H, d, J=6.2 Hz), 5.44 (2H, s), 7.29 (1H, d, J=7.2 Hz), 7.41–7.51 (2H,m), 7.72 (1H, d, J=2.0 Hz), 7.55–7.69 (2H, m), 7.81 (1H, d, J=1.8 Hz),7.91–7.95 (2H, m), 8.24 (1H, d, J=8.2 Hz), 8.39 (1H, d, J=8.8 Hz).

(7)3-(Aminomethyl)-6-chloro-2-methyl-4(1-naphthylmethoxy)-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 226–227° C. Elemental analysis for C₂₂H₂₀N₂O₂Cl₂ ¼H₂OCalculated C, 62.94; H, 4.92; N, 6.67. Found: C, 63.01; H, 4.79; N,6.59. ¹H-NMR(DMSO-d₆) δ: 3.65 (3H, s), 4.29 (2H, d, J=4.2 Hz), 5.55 (2H,s), 7.52–7.78 (6H, m), 7.98–8.06 (2H, m), 8.22–8.30 (2H, m), 8.81 (3H,bs).

Example 123-(Aminomethyl)-7-chloro-2-methyl-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) To a solution of ethyl7-chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 5 (1))(2.82 g, 10 mmol) in tetrahydrofuran (20 ml) was added sodium hydride(0.48 g, 12 mmol)(60% in oil) at 0° C. and the mixture was stirred at 0°C. for 30 min. To the obtained mixture was addedN-phenyltrifluoromethane sulfonimide (4.29 g, 12 mmol) and the mixturewas stirred at room temperature for 2 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. After washing the extractwith water, the extract was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give ethyl7-chloro-2-methyl-1-oxo-4-trifluoromethane-sulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(2.95 g, 71.4%) as an oil.

¹H-NMR(CDCl₃) δ: 1.45 (3H, d, J=7.2 Hz), 3.61 (3H, s), 4.49 (2H, q,J=7.2 Hz), 7.75–7.76 (2H, m), 8.44–8.45 (1H, m).

(2) A mixture of ethyl7-chloro-2-methyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(2.90 g, 7 mmol), phenylboronic acid (1.02 g, 8.4 mmol) and sodiumcarbonate (1.85 g, 17.5 mmol) in toluene (20 ml), ethanol (4 ml) andwater (4 ml) was stirred under an argon atmosphere at room temperaturefor 30 min. To the obtained mixture was addedtetrakis(triphenylphosphine)palladium (0.46. g, 4 mmol) and the mixturewas refluxed under heating under an argon atmosphere for 12 h. Thereaction mixture was poured into water and extracted with ethyl acetate.After washing the extract with water, the extract was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give ethyl7-chloro-2-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate(1.70 g, 71.1%) as crystals.

Melting point 152–153° C. ¹H-NMR(CDCl₃) δ: 0.92 (3H, t, J=7.1 Hz), 3.62(3H, s), 4.02 (2H, q, J=7.1 Hz), 7.17 (1H, dd, J=8.8 Hz), 7.28–7.33 (2H,m), 7.41–7.53 (4H, m), 8.48 (1H, d, J=2.2 Hz).

(3)7-Chloro-2-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 261–262° C. ¹H-NMR(CDCl₃) δ: 3.68 (3H, s), 7.13 (1H, d,J=8.8 Hz), 7.32–7.51 (6H, m), 8.45 (1H, d, J=2.2 Hz).

(4) 7-Chloro-3-hydroxymethyl-2-methyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 199–200° C. Elemental analysis for C₁₇H₁₄NO₂Cl Calculated:C, 68.12; H, 4.71; N, 4.67. Found: C, 68.25; H, 4.71; N, 4.49.¹H-NMR(CDCl₃) δ: 2.17 (1H, t, J=5.5 Hz), 3.82 (3H, s), 4.40 (2H, d,J=5.5 Hz), 6.96 (1H, d, J=8.8 Hz), 7.26–7.33 (2H, m), 7.39 (1H, dd,J=2.2, 8.8 Hz), 7.45–7.54 (3H, m), 8.39 (1H, d, J=2.2 Hz).

(5) 7-Chloro-3-chloromethyl-2-methyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.84 (3H,), 4.40 (2H, s), 6.99 (1H, d, J=8.4 Hz),7.31–7.35 (2H, m), 7.42–7.56 (4H, m), 8.47 (1H, d, J=2.2 Hz).

(6)2-{(7-Chloro-2-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 241–242° C. Elemental analysis for C₂₅H₁₇N₂O₃ClCalculated: C, 70.01; H, 4.00; N, 6.53. Found: C, 69.69; H, 4.13; N,6.56. ¹H-NMR(DMSO-d₆) δ: 3.61 (3H, s), 4.76 (2H, s), 6.89 (1H, d, J=8.8Hz), 7.26–7.31 (2H, m), 7.40–7.43 (3H, m), 7.66 (1H, dd, J=2.2, 8.8 Hz),7.74–7.83 (4H, m), 8.23 (1H, d, J=2.2 Hz).

(7) 3-(Aminomethyl)-7-chloro-2-methyl-4-phenyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 4 (7))

Melting point 242–243° C. Elemental analysis for C₁₇H₁₆N₂OCl₂ ½H₂OCalculated: C, 59.31; H, 4.98; N, 8.14. Found: C, 59.50; H, 4.97; N,8.14. ¹H-NMR(DMSO-d₆) δ: 3.72 (3H, s), 3.93 (2H, s), 6.94 (1H, d, J=8.6Hz), 7.37–7.41 (2H, m), 7.56–7.59 (3H, m), 7.72 (1H, dd, J=2.4, 8.6 Hz),8.27 (1H, d, J=2.4 Hz), 8.65 (3H, bs).

Example 133-(Aminomethyl)-6-chloro-2-methyl-4-propoxy-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-2-methyl-4-propoxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 1.08 (3H, t, J=7.3 Hz), 1.45 (3H, t, J=7.2 Hz),1.76–1.89 (2H, m), 3.51 (3H, s), 3.93 (2H, t, J=6.6 Hz), 4.48. (2H, q,J=7.2 Hz), 7.49 (1H, dd, J=2.0, 8.6 Hz), 7.71 (1H, d, J=2.0 Hz), 8.37(1H, d, J=8.6 Hz).

(2)6-Chloro-2-methyl-1-oxo-4-propoxy-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 1.64–165° C. Elemental analysis for C₁₄H₁₄NO₄ClCalculated: C, 56.86; H, 4.77; N, 4.74. Found: C, 56.82; H, 4.70; N,4.52. ¹H-NMR(CDCl₃) δ: 1.08 (3H, t, J=7.3 Hz), 1.77–1.95 (2H, m), 3.65(3H, s), 3.97 (2H, t, J=6.6 Hz), 7.51 (1H, dd, J=2.0, 8.6 Hz), 7.64 (1H,d, J=2.0 Hz), 7.67 (1H, bs), 8.31 (1H, d, J=8.6 Hz).

(3) 6-Chloro-3-hydroxymethyl-2-methyl-4-propoxy-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 95.5–96.5° C. Elemental analysis for C₁₄H₁₆NO₃ClCalculated: C, 59.68; H, 5.72; N, 4.97. Found: C, 59.38; H, 5.69; N,4.87. ¹H-NMR(CDCl₃) δ: 1.14 (3H, t, J=7.3 Hz), 1.79–1.93 (2H, m), 2.89(1H, bs), 3.69 (3H, s), 3.79 (2H, t, J=6.6 Hz), 4.79 (2H, d, J=4.8 Hz),7.39 (1H, dd, J=2.0, 8.6 Hz), 7.55 (1H, d, J=2.0 Hz), 8.24 (1H, dd,J=3.8, 8.6 Hz).

(4) 6-Chloro-3-chloromethyl-2-methyl-4-propoxy-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.16 (3H, t, J=7.3 Hz), 1.86–2.00 (2H, m), 3.73 (3H,s), 3.95 (2H, t, J=6.6 Hz), 4.80 (2H, s), 7.48 (1H, dd, J=2.0, 8.6 Hz),7.71 (1H, d, J=2.0 Hz), 8.38 (1H, d, J=8.6 Hz).

(5)2-{(6-Chloro-2-methyl-4-propoxy-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 193–194° C. Elemental analysis for C₂₂H₁₉N₂O₄ClCalculated: C, 64.31; H, 4.66; N, 6.82. Found: C, 63.96; H, 4.51; N,6.48. ¹H-NMR(DMSO-d₆) δ: 1.00 (3H, t, J=7.4 Hz), 1.72–1.86 (2H, m), 3.51(3H, s), 3.90 (2H, t, J=6.7 Hz), 5.03 (2H, s), 7.59 (1H, dd, J=1.8, 8.4Hz), 7.68 (1H, d, J=1.8 Hz), 7.86 (4H, s), 8.24 (1H, d, J=8.4 Hz).

(6)Tert-butyl(6-chloro-2-methyl-4-propoxy-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 104–105° C. Elemental analysis for C₁₉H₂₅N₂O₄ClCalculated: C, 59.92; H, 6.62; N, 7.36. Found: C, 59.87; H, 6.34; N,7.23. ¹H-NMR(CDCl₃) δ: 1.13 (3H, t, J=7.4 Hz), 1.47 (9H, s), 1.85–1.96(2H, m), 3.62 (3H, s), 3.80 (2H, t, J=6.6 Hz), 4.53 (2H, d, J=6.0 Hz),4.77 (1H, bs), 7.43 (1H, dd, J=2.0, 8.6 Hz), 7.65 (1H, d, J=2.0 Hz),8.33 (1H, d, J=8.6 Hz).

(7) 3-(Aminomethyl)-6-chloro-2-methyl-4-propoxy-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 226–227° C. Elemental analysis for C₁₄H₁₈N₂O₂Cl₂ ½H₂OCalculated: C, 51.55; H, 5.87; N 8.59. Found: C, 51.61; H, 6.13; N,8.44. ¹H-NMR(DMSO-d₆) δ: 1.09 (3H, t, J=7.4 Hz), 1.79–1.93 (2H, m), 3.39(3H, s), 3.88 (2H, t, J=6.4 Hz), 4.24 (2H, s), 7.66 (1H, dd, J=2.0, 8.6Hz), 7.74 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=8.6 Hz), 8.78 (3H, bs).

Example 143-(Aminomethyl)-6-chloro-4-cyclopentylmethoxy-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-4-cyclopentylmethoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

Melting point 89–90° C. Elemental analysis for C₁₉H₂₂NO₄Cl ¼H₂OCalculated: C, 61.96; H, 6.15; N, 3.80. Found: C, 61.91; H, 6.03; N,3.93. ¹H-NMR(CDCl₃) δ: 1.33–1.43 (2H, m), 1.45 (3H, t, J=7.2 Hz),1.61–1.72 (4H, m), 1.89–1.93 (2H, m), 2.32–2.47 (1H, m), 3.51 (3H, s),3.85 (2H, d, J=6.8 Hz), 4.47 (2H, q, J=7.2 Hz), 7.50 (1H, dd, J=2.0, 8.6Hz), 7.72 (1H, d, J=2.0 Hz), 8.37 (1H, d, J=8.6 Hz).

(2)6-Chloro-4-cyclopentylmethoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 191–192° C. Elemental analysis for C₁₇H₁₈NO₄Cl ¼H₂OCalculated: C, 60.00; H, 5.48; N, 4.12. Found: C, 60.20; H, 5.28; N,4.09. ¹H-NMR(DMSO-d₆) δ: 1.33–1.46 (2H, m), 1.58–1.60 (4H, m), 1.71–1.86(2H, m), 2.30–2.45 (1H, m), 3.43 (3H, s), 3.82 (2H, d, J=6.8 Hz), 7.65(1H, dd, J=2.0, 8.6 Hz), 7.71 (1H, d, J=2.0 Hz), 8.26 (1H, d, J=8.6 Hz)

(3)6-Chloro-4-cyclopentylmethoxy-3-hydroxymethyl-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 127–128° C. Elemental analysis for C₁₇H₂₀NO₃Cl ¼H₂OCalculated: C, 62.57; H, 6.33; N, 4.29. Found: C, 62.61; H, 6.21; N,4.23. ¹H-NMR(CDCl₃) δ: 1.35–1.51 (2H, m), 1.61–1.74 (4H, m), 1.84–1.97(2H, m), 2.36–2.51 (1H, m), 3.71 (5H, s), 4.81 (2H, d, J=5.0 Hz), 7.40(1H, dd, J=2.0, 8.6 Hz), 7.60 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=8.6 Hz).

(4)6-Chloro-3-chloromethyl-4-cyclopentylmethoxy-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.36–1.71 (6H, m), 1.85–1.97 (2H, m), 2.37–2.57 (1H,m), 3.73 (3H, s), 3.87 (2H, d, J=7.0 Hz), 4.80 (2H,), 7.48 (1H, dd,J=2.2, 8.8 Hz), 7.72 (1H, d, J=2.2 Hz), 8.37 (1H, d, J=8.8 Hz).

(5)2-{(6-Chloro-4-cyclopentylmethoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 204–205° C. Elemental analysis for C₂₅H₂₃N₂O₄Cl 3/4H₂OCalculated: C, 64.65; H, 5.32; N, 6.03. Found: C, 64.85; H, 5.08; N,6.09. ¹H-NMR(DMSO-d₆) δ: 1.23–1.63 (6H, m), 1.72–1.84 (2H, m), 2.33–2.46(1H, m), 3.48 (3H, s), 3.83 (2H, d, J=6.8 Hz), 7.59 (1H, dd, J=2.0, 8.6Hz), 7.68. (1H, d, J=2.0 Hz), 7.82–7.91 (4H, m), 8.37(1H, d, J=8.8 Hz).

(6)Tert-butyl(6-chloro-4-cyclopentylmethoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 161–162° C. Elemental analysis for C₂₂H₂₉N₂O₄ClCalculated: C, 62.77; H, 6.94; N, 6.66. Found: C, 62.49; H, 7.15; N,6.60. ¹H-NMR(CDCl₃) δ: 1.26–1.44 (2H, m), 1.47 (9H, s), 1.60–1.71 (4H,m), 1.87–1.99 (2H, m), 2.38–2.53 (1H,m), 3.62 (3H, s), 3.72 (2H, d,J=6.8 Hz), 4.53 (2H, d, J=5.8 Hz), 7.43 (1H, dd, J=1.8, 8.6 Hz), 7.66(1H, d, J=1.8 Hz), 8.33 (1H, d, J=8.6 Hz).

(7)3-(Aminomethyl)-6-chloro-4-cyclopentylmethoxy-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 211–219° C. Elemental analysis for C₁₇H₂₂N₂O₂Cl₂ ½H₂OCalculated: C,55.74; H, 6.33; N, 7.65. Found: C, 55.75; H 6.32; N, 7.69.¹H-NMR(DMSO-d₆) δ: 1.37–1.68 (6H, m), 1.81–1.93 (2H, m), 2.39–2.54 (1H,m), 3.61 (3H, s), 3.80 (2H, d, J=6.8 Hz), 4.24 (2H, d, J=5.2.Hz), 7.65(1H, dd, J=2.0, 8.4 Hz), 7.72 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=8.4 Hz),8.77 (3H, bs).

Example 153-(Aminomethyl)-6-chloro-2-methyl-4-(4-nitrophenoxy)-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-2-methyl-4-(4-nitrophenoxy)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 4 (2))

Melting point 184–185° C. Elemental analysis for C₁₉H₁₅N₂O₆Cl ¼H₂OCalculated: C, 56.66; H, 3.75; N, 6.95. Found: C, 56.70; H, 3.85; N,6.81. ¹H-NMR(CDCl₃) δ: 1.12 (3H, t, J=7.2 Hz), 3.60 (3H, s), 4.28 (2H,q, J=7.2 Hz), 7.05 (2H, d, J=9.2 Hz), 7.35 (1H, d, J=2.0 Hz), 7.55 (1H,dd, J=2.0, 8.8 Hz), 8.24 (2H, d, J=9.2 Hz), 8.44 (1H, d, J=8.8 Hz).

(2)6-Chloro-2-methyl-4-(4-nitrophenoxy)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3)).

Melting point 240–241° C. Elemental analysis for C₁₇H₁₁N₂O₆Cl ½AcOEtCalculated: C, 54.49; H, 3.61; N, 6.69. Found: C, 54.63; H, 3.64; N,6.69. ¹H-NMR(CDCl₃) δ: 3.51 (3H, s), 7.28 (2H, d, J=9.2 Hz), 7.36 (1H,d, J=2.0 Hz), 7.68 (1H, d, J=2.0, 8.6 Hz), 8.22 (2H, d, J=9.2 Hz), 8.33(1H, d, J=8.6 Hz).

(3)6-Chloro-3-hydroxymethyl-2-methyl-4-(4nitrophenoxy)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 249–250° C. Elemental analysis for C₁₇H₁₃N₂O₅ClCalculated: C, 56.60; H, 3.63; N, 7.77. Found: C, 56.68; H, 3.83; N,7.65. ¹H-NMR(CDCl₃) δ: 3.80 (3H, s), 4.35 (1H, bs), 4.64 (2H, d, J=5.2Hz), 7.07 (2H, d, J=9.1 Hz), 7.32 (1H, d, J2.0 Hz), 7.47 (1H, dd, J=2.0,8.6 Hz), 8.22 (2H, d, J=9.1 Hz), 8.40 (1H, d, J=8.6 Hz).

(4)6-Chloro-3-chloromethyl-2-methyl-4-(4-nitrophenoxy)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.79 (3H, s), 4.65 (2H, s), 7.06 (2H, d, J=9.1 Hz),7.34 (1H, d, J=1.8 Hz), 7.52 (1H, dd, J=1.8, 8.8 Hz), 8.24 (2H, d, J=9.1Hz), 8.44 (1H, d, J=8.8 Hz).

(5)2-{(6-Chloro-2-methyl-4-(4-nitrophenoxy)-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4(6))

Melting point 257–258° C. Elemental analysis for C₂₅H₁₆N₃O₆ClCalculated: C, 61.30; H, 3.29; N, 8.58. Found: C, 61.10; H, 3.38; N,8.41. ¹H-NMR(DMSO-d₆) δ: 3.81 (3H, s), 4.94 (2H, s), 6.92 (2H, d, J=9.4Hz), 7.24 (1H, d, J=1.8 Hz), 7.60–7.72 :(5H, m), 7.88 (2H, d, J=9.4 Hz),8.33 (1H, d, J=8.4 Hz).

(6)Tert-butyl[6-chloro-2-methyl-4-(4-nitrophenoxy)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 198–199° C. Elemental analysis for C₂₂H₂₂N₃O₆ClCalculated: C, 57.46; H, 4.82; N, 9.14. Found: C, 57.44; H, 4.80; N,9.25. ¹H-NMR(:CDCl₃) δ: 1.41 (9H, s), 3.70 (3H, s), 4.41 (2H, d, J=5.8Hz), 4.64 (1H, bs), 7.03 (2H, d, J=9.4 Hz), 7.29 (1H, d, J=2.0 Hz), 7.48(1H, d, J=2.0, 8.6 Hz), 8.24 (2H, d, J=9.4 Hz), 8.40 (1H, d, J=8.6 Hz).

(7)3-(Aminomethyl)-6-chloro-2-methyl-4-(4nitrophenoxy)-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 242–243° C. Elemental analysis for C₁₇H₁₅N₃O₄Cl₂ ¼H₂OCalculated: C, 50.95; H, 3.90; N, 10.49. Found: C, 51.05; H, 3.92; N,10.23. ¹H-NMR(DMSO-d₆) δ: 3.68 (3H, s), 4.08 (2H, bs), 7.35 (2H, d,J=9.4 Hz), 7.38 (1H, d, J=2.0 Hz), 7.68 (1H, d, J=2.0, 8.6 Hz), 8.26(2H, d, J=9.4 Hz), 8.34 (1H, d, J=8.6 Hz), 8.83 (3H, bs).

Example 163-(Aminomethyl)-6-Chloro-4-methoxyphenyl)-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) To a solution of ethyl6-Chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 5 (1))(8.45 g, 30 mmol) in tetrahydrofuran (100 ml) was added sodium hydride(1.44 g, 36 mmol)(60% in oil) at 0° C. and the mixture was stirred at 0°C. for 30 min. To the obtained mixture was addedN-phenyltrifluoromethane sulfonimide (12.86 g, 36 mmol) and the mixturewas stirred at room temperature for 2 h. The reaction mixture waspoured, into water and extracted with ethyl acetate. After washing theextract with water, the extract was dried over anhydrous-magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give ethyl6-chloro-2-methyl-1-oxo-4-trifluoromethane-sulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(8.54 g, 68.8%) as crystals.

¹H-NMR(CDCl₃) δ: 1.45 (3H, t, J=7.0 Hz), 3.60 (3H, s), 4.49 (2H, q,J=7.0 Hz), 7.60 (1H, dd, J=2.0, 8.6 Hz), 7.75 (1H, d, J=2.0 Hz), 8.40(1H, d, J=8. 6 Hz). (2) Ethyl6-chloro-4-(4-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 12 (2))

Melting point 135–136° C. Elemental analysis for C₂₀H₁₈NO₄Cl Calculated:C, 64.61; H, 4.88; N, 3.77. Found: C, 64.81; H, 4.87; N, 3.57.¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.2 Hz), 3.59 (3H, s), 3.88 (3H, s),4.07 (2H, q, J=7.2 Hz), 6.98 (2H, d, J=8.8 Hz), 7.232 (2H, d, J=8.8 Hz),7.24 (1H, d, J=2.0 Hz), 7.47 (1H, d, J=2.0, 8.6 Hz), 8.34 (1H, d, J=8.6Hz). (3)6-Chloro-4-(4-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 242–243° C. Elemental analysis for C₁₆H₁₄NO₄Cl Calculated:C, 62.89; H, 4.10; N, 4.07. Found: C, 63.06; H, 4.18; N, 4.01.¹H-NMR(CDCl₃) δ: 3.52 (3H, s), 3.83 (3H, s), 7.04 (1H, d, J=2.2 Hz),7.06 (2H, d, J=8.6 Hz), 7.26(2H, d, J=8.6 Hz), 7.62 (1H, d, J=2.2, 8.6Hz), 8.32 (1H, d, J=8.6 Hz).

(4)6-Chloro-4-(4-methoxyphenyl)-3-hydroxymethyl-2methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 187–188° C. Elemental analysis for C₁₈H₁₆NO₃Cl Calculated:C, 65.56; H, 4.89; N, 4.25. Found: C, 65.62; H, 5.04; N, 4.09.¹H-NMR(CDCl₃) δ: 2.26 (1H, bs), 3.80 (3H,s), 3.90 (3H, s), 4.47 (2H, d,J=5.6 Hz), 7.01–7.06 (3H, m), 7.18–7.25.(3H, m), 7.35 (1H, dd, J=1.8,8.6 Hz), 8.33 (1H, d, J=8.6 Hz).

(5)6-Chloro-3-chloromethyl-4-(4-methoxyphenyl-)-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.82 (3H, s), 3.91 (3H, s), 4.41 (2H, s), 7.03–7.08(3H, m), 7.24 (22H, d, J=8.0 Hz), 7.43 (1H, dd, J=2.0, 8.6 Hz), 8.42(1H,d, J=8.6 Hz).

(6)2-{(6-Chloro-4-(4-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 207–208° C. Elemental analysis for C₂₆H₁₉N₂O₄ClCalculated: C, 68.05; H, 4.17; N, 6.10. Found: C, 68.24; H, 4.25; N,5.96. ¹H-NMR(DMSO-d₆) δ: 3.58 (3H, s), 3.77 (3H, s), 4.77 (2H, s), 6.83(1H, d, J=2.0 Hz), 6.98 (2H, d, J=8.8: Hz), 7.20 (2H, d, J=8.8 Hz), 7.55(1H, dd, J=2.0, 8.6 Hz), 7.75–7.85 (4H, m), 8.29 (1H, d, J=8.6 Hz).

(7)Tert-butyl{6-chloro-4-(4-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 187–188° C. Elemental analysis for C₂₃H₂₅N₂O₄ClCalculated: C, 64.41; H, 5.88; N, 6.53. Found: C, 64.72; H, 5.96;N,6.51. ¹H-NMR(CDCl₃) δ: 1.43 (9H, s), 3.69 (3H, s), 3.91 (3H, s), 4.21(2H, d, J=5.8 Hz), 4.65 (1H, bs), 6.95 (1H, d, J=2.0 Hz), 7.02 (2H, d,J=8.9 Hz), 7.15 (2H, d, J=8.9 Hz), 7.36 (1H, dd, J=2.0, 8.6 Hz), 8.35(1H, d, J=8.6 Hz).

(8)3-(Aminomethyl)-6-chloro-4-(4-methoxyphenyl)-2methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1: (7))

Melting point 249–250° C. Elemental analysis forC₁₈H₁₈N₂O₂Cl₂Calculated: C, 59.19; H, 4.97; N, 7.67.Found: C, 59.23; H,4.81; N, 7.30. ¹H-NMR(DMSO-d₆) δ: 3.71 (3H, s), 3.87 (3H, s), 3.95 (2H,bs), 6.88 (1H, d, J=2.0 Hz), 7.14 (2H, d, J=8.8 Hz), 7.32 (2H, d, J=8.8Hz), 7.62 (1H, dd, J=2.0, 8.6 Hz), 8.33 (1H, d, J=8.6 Hz), 8.66 (3H,bs).

Example 173-(Aminomethyl)-6-chloro-4-(3-methoxyphenyl)-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-4-(3-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 12 (2))

Melting point 146–147° C. Elemental analysis for C₂₀H₁₈NO₄Cl Calculated:C, 64.61; H, 4.88; N, 3.77. Found: C, 64.55; H, 4.84; N, 3.69.¹H-NMR(CDCl₃) δ: 0.97 (3H, t, J=7.2 Hz), 3.60 (3H, s), 3.83 (3H, s),4.06 (2H, q, J=7.2 Hz), 6.84–7.09 (3H, m), 7.23 (1H, d, J=2.0 Hz), 7.37(1H, t, J=7.91 Hz), 7.47 (1H, dd, J=2.0, 8.6 Hz), 8.44 (1H, d, J=8.6Hz).

(2)6-Chloro-4-(3-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that-in Example 4(3).

Melting point 212–213° C. Elemental analysis for C₁₈H₁₄NO₄Cl Calculated:C, 62.89; H, 4.10; N, 4.07. Found: C, 63.14; H, 4.22; N, 3.90.¹H-NMR(DMSO-d₆) δ: 3.52 (3H, s), 3.78 (3H, s), 6.90–6.94 (2H, m),7.03–7.07. (2H, m), 7.44 (1H, t, J=8.1 Hz), 7.62 (1H, dd, J=2.0, 8.6Hz), 8.32 (1H, d, J=8.6 Hz)

(3)6-Chloro-4-(3-methoxyphenyl)-3-hydroxymethyl-2methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 127–128° C. Elemental analysis for C₁₈H₁₆NO₃Cl Calculated:C, 65.56; H, 4.89; N, 4.25. Found: C, 65.72; H, 5.14; N, 4.04.¹H-NMR(CDCl₃) δ: 2.00 (1H, bs), 3.81 (3H, s), 3.86 (3H, s), 4.47 (2H,s), 6.82–6.89 (2H, m), 6.99–7.04 (2H, m), 7.38 (1H, dd, J=2.1, 8.6 Hz),7.43 (1H, t, J=7.9 Hz), 8.37 (1H, d, J=8.6 Hz).

(4) 6-Chloro-3-chloromethyl-4-(3-methoxyphenyl)-2methyl-1(2H)-isoquinolinone (synthesized according to the method similar to thatin Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.82 (3H, s), 3.86 (3H, s), 4.40 (2H, s), 6.88–6.92(1H, m), 7.01–7.07 (2H, m), 7.44 (1H, dd, J=2.0, 8.6 Hz), 7.45(1H, t,J=8.0 Hz), 8.42 (1H, d, J=8.6 Hz).

(5)2-{(6-Chloro-4-(3-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 184–185° C. Elemental analysis for C₂₆H₁₉N₂O₄ClCalculated: C, 68.05; H, 4.17; N, 6.10. Found: C, 67.69; H 4.40; N,5.82. ¹H-NMR(DMSO-d₆) δ: 3.61 (3H, s), 3.63 (3H, s), 4.78 (2H, s),6.08–6.84 (3H, m), 6.90–6.95 (1H, m), 7.33 (1H, t, J=8.1 Hz), 7.55 (1H,dd, J=2.0, 8.6 Hz), 7.74–7.84 (4H, m), 8.30 (1H, d, J=8.6 Hz).

(6)Tert-butyl{6-chloro-4.4(3-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 231–232° C. Elemental analysis for C₂₃H₂₅N₂O₄ClCalculated: C, 64.41; H, 5.88; N, 6.53. Found: C, 64.25; H, 5.49;N,6.34. ¹H-NMR(CDCl₃) δ: 1.43 (9H, s), 3.70 (3H, s), 3.86 (3H, s),4.21–4.23 (2H, m), 4.60, (1H, bs), 6.77–6.84 (2H,m), 6.96 (1H, d, J=1.8Hz), 6.99–7.05 (1H, m), 7.35–7.48 (2H, m), 8.37 (1H, d, J=8.8 Hz).

(7)3-(Aminomethyl)-6-chloro-4-(3-methoxyphenyl)-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point. 237–238° C. Elemental analysis for C₁₈H₁₈N₂O₂Cl₂ ½H₂OCalculated: C, 5.77; H, 5.12; N, 7.67. Found: C, 57.62; H, 5.23; N,7.40. ¹H-NMR(DMSO-d₆) δ: 3.71 (3H, s), 3.82 (3H, s), 3.92–3.98 (2H, m),6.87 (1H, d, J=2.0 Hz), 6.94 (1H, d, J=7.5 Hz), 7.01 (1H, bs), 7.11 (1H,dd, J=2.6, 8.1 Hz), 7.51 (1H, dd, J=7.5, 8.1 Hz), 7.62 (1H, dd, J=2.0,8.6 Hz), 8.33 (11H, d, J=8.6 Hz), 8.63 (3H, bs).

Example 183-(Aminomethyl)-6-chloro-4-(4-hydroxyphenyl)-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) To a solution of2-{[6-chloro-4-(4-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 16(7))(0.92 g, 2 mmol) in dichloromethane (10 ml) was added boron tribromide,(76 ml, 36 mmol) at 0° C. and the mixture was stirred at 0° C. for 1 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was recrystallized fromtetrahydrofuran-diisopropyl ether to give2-{[6chloro-4-(4-hydroxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione(0.83 g, 94.3%) as crystals.

Melting point 307–308° C. Elemental analysis for C₂₅H₁₇N₂O₄Cl H₂OCalculated: C, 64.87; H, 4.14.; N, 6.05. Found: C, 64,44; H, 3.88; N,5.66. ¹H-NMR(DMSO-d₆) δ: 3.67 (3H, s), 4.76 (2H, s), 6.81. (2H, d, J=8.6Hz), 6.86 (1H, d, J=2.0 Hz), 7.08 (2H, d, J=8.6 2,5 Hz), 7.54 (H, dd,J=2.0, 8.6 Hz), 7.75–7.85 (4H, m), 8.28 (1H, dd, J=8.6 Hz), 9.60 (1H,s).

(2) Tert-butyl4-{3-{{(tertbutoxycarbonyl)amino}methyl}-6-chloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl}phenylcarbonate(synthesized according to the method similar to that in Example 1 (6))

Melting point 195–196° C. Elemental analysis for C₂₇H₃₁N₂O₆ClCalculated: C, 62.97; H, 6.07; N, 5.44. Found: C, 63.02; H, 6.28; N,5.34. ¹H-NMR(CDCl₃) δ: 1.41 (9H, s), 1.61 (9H, s), 3.69 (3H, s), 4.20(2H, d, J=6.0 Hz), 4.62 (1H, bs), 6.92 (1H, d, J=1.8 Hz), 7.24–7.40 (5H,m), 8.35 (1H, d, J=8.6 Hz).

(3)3-(Aminomethyl)-6-chloro-4-(4-hydroxyphenyl)-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 253–254° C. Elemental analysis for C₁₇H₁₆N₂O₂Cl₂Calculated: C, 58.13; H, 4.59; N, >7.98. Found: C, 57.99; H, 4.57; N,7.88. ¹H-NMR(DMSO-d₆) δ: 3.70 (3H, s), 3.97 (2H, bs), 6.92 (1H, d, J=2.0Hz), 6.97 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz), 7.60 (1H, dd,J=2.0, 8.6 Hz), 8.32 (1H, d, J=8.6 Hz), 8.62 (3H, bs), 9.89 (1H, bs).

Example 193-(Aminomethyl)-6-chloro-4-(3-hydroxyphenyl)-2-methyl-1(2H)-isoquinolinonehydrochloride

(1)2-{[6-Chloro-4-(3-hydroxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 18,(1))

Melting point 297–298° C. Elemental analysis for C₂₅H₁₇N₂O₄Cl ¼H₂OCalculated: C, 66.82; H, 4.00; N, 6.23. Found: C, 66.52; H, 4.34; N,5.85. ¹H-NMR(DMSO-d₆) δ: 3.58 (3H, s), 4.73 (1H, d, J=15.8 Hz), 4.82(1H, d, J=15.8 Hz), 6.65–6.70 (2H, m), 6.76–6.80 (1H, m), 6.85 (1H, d,J=2.0 Hz), 7.20 (1H, t, J=7.7 Hz), 7.55 (1H, dd, J=2.0, 8.6, Hz),7.75–7.85 (4H, m), 8.29 (1H, d, J=8.6 Hz), 9.57 (1H, s).

(2)Tert-butyl{6-chloro-4-(3-hydroxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 244–2450° C. Elemental analysis for C₂₂H₂₃N₂O₄ClCalculated: C, 63.69; H, 5.59; N, 6.75.Found: C, 63.76; H, 5.75; N,6.52. ¹H-NMR(CDCl₃) δ: 1.44 (9H, s), 3.69 (3H, s), 4.23 (2H, d, J=5.6Hz) 4.86 (1H, bs), 6.69–6.75 (2H, m), 6.95–7.00(1H, m), 7.02 (1H, d,J=2.0 Hz), 7.33 (1H, t, J=7.7 Hz), 7.37 (1H, dd, J=2.0, 8.6 Hz), 8.36(1H, d, J=8.6 Hz), 8.87 (1H, s).

(3)3-(Aminomethyl)-6-chloro-4-(3-hydroxyphenyl)-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1(7))

Melting point 277° C. Elemental analysis for C₁₇H₁₆N₂O₂Cl₂ Calculated:C, 58.13; H, 4.59; N, 7.98. Found: C, 57.96; H, 4.66; N, 8.01.¹H-NMR(DMSO-d₆) δ: 3.69 (3H, s), 3.97 (2H, bs), 6.78–6.81 (2H, m), 6.90(1H, d, J=2.0 Hz), 6.94–6.99 (1H, m), 7.38 (1H, t, J=7.9 Hz), 7.62 (1H,dd, J=2.0, 8.6.Hz), 8.32(1H, d, J=8.6 Hz), 8.60(3H, bs), 9.87(1H, bs).

Example 203-(Aminomethyl)-6-chloro-4-(4-fluorophenyl)-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-4-(4-fluorophenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 12 (2))

Melting point 159–160° C. Elemental analysis for C₁₉H₁₅NO₃ClFCalculated: C, 63.43; H, 4.20; N, 3.89. Found: C, 63.56; H, 3.96; N,3.66. ¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.0 Hz), 3.59 (3H, s), 4.07 (2H,q, J=7.0 Hz), 7.12 (1H, d, J=2.0 Hz), 7.17–7.21. (2H, m), 7.27–7.347(2H, m), 7.48 (1H, dd, J=2.0, 8.6 Hz), 8.44 (1H, d, J=8.6, Hz).

(2)6-Chloro-4-(4-fluorophenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 239–240° C. Elemental analysis for C₁₇H₁₁NO₃ClFCalculated: C, 61.55; H, 3.34; N, 4.22. Found: C, 61.82; H, 3.52; N,4.02. ¹H-NMR(DMSO-d₆) δ: 3.52,(3H, s), 6.99 (1H, d, J=2.0 Hz), 7.30–7.45(4H, m), 7.63 (1H, dd, J=2.0, 8.6 Hz), 8.33 (1H, d, J=8.6 Hz).

(3)6-Chloro-4-(4-fluorophenyl)-3-hydroxymethyl-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 167–168° C. Elemental analysis for C₁₇H₁₃NO₂ClFCalculated: C, 64.26; H, 4.12; N, 4.41. Found: C, 64.33; H, 4.08; N,4.36. ¹H-NMR(CDCl₃) δ: 2.08 (1H, bs), 3.81 (3H, s), 4.45 (2H, d, J=5.2Hz), 6.94 (1H, d, J=2.0 Hz), 7.1.7–7.33 (4H, m), 7.38 (1H, d, J=2.0, 8.6Hz), 8.36 (1H, d, J=8.6 Hz).

(4)6-Chloro-3-chloromethyl-4-(4-fluorophenyl)-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 382 (3H, s), 4.37 (2H, s), 6.97 (1H, d, J=2.0 Hz),7.20–7.37 (4H, m), 7.45 (1H, dd, J=2.0, 8.6 Hz), 8.43 (1H, d, J=8.6 Hz).

(5)2-{[6-Chloro-4-(4-fluorophenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 190–191° C. Elemental analysis for C₂₅H₁₆N₂O₃ClFCalculated: C, 67.20; H, 3.61; N, 6.27. Found: C, 67.40; H, 3.42; N,6.24. ¹H-NMR(DMSO-d₆) δ: 3.61 (3H, S), 4.75 (2H, s), 6.78 (1H, d, J=2.0Hz), 7.23–7.39 (4H, m), 7.57 (1H, dd, J=2.0, 8.6 Hz), 7.76–7.85 (4H, m),7.86 (4H, s), 8.31 (1H, d, J=8.6 Hz).

(6)Tert-butyl{6-chloro-4-(4-fluorophenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 2.06–207° C. Elemental analysis for C₂₂H₂₂N₂O₃ClFCalculated: C, 63.39; H, 5.32; N, 6.72. Found: C, 63.56; H, 5.27; N,6.61. ¹H-NMR(CDCl₃) δ: 1.44 (9H, s), 3.69 (3H; s), 4.19 (2H, d, J=5.6Hz), 4.67 (1H, bs), 6.8–8 (1H, d, J=2.6 Hz), 7.22–7.27 (4H, m), 7.38(1H, dd; J=2.0, 8.6 Hz), 8.35 (1H, d, J=8.6 Hz).

(7) 3-(Aminomethyl)-6-chloro-4-(4-fluorophenyl)-2-methyl-1(2H)-isoquinolinone hydrochloride (synthesized according to the methodsimilar to that in Example 1 (7))

Melting point 277–278° C. Elemental analysis for C₁₇H₅N₂OCl₂FCalculated: C, 57.81; H, 4.28; N, 7.93. Found: C, 5,7.98; H, 4.29; N,7.84. ¹H-NMR(DMSO-d₆) δ: 3.71 (3H, s), 3.92 (2H, s), 6.–83 (1H, d, J=2.0Hz), 7.37–7.46 (4H, m), 7.62 (1H, dd, J=2.0, 8.6 Hz), 8.34 (1H, d, J=8.6Hz), 8.73 (3H, bs).

Example 213-(Aminomethyl)-6-chloro-2-methyl-4-(4trifluoromethylphenyl)-1(2H)-isoquinolinonehydrochloride

(1)6-Chloro-2-methyl-1-oxo-4-(4-trifluoromethylphenyl)-1,2-dihydro-3-isoquinolinecarboxylate,ethyl (synthesized according to the method similar to that in Example 12(2))

Melting point 170–171° C. Elemental analysis for C₂₀H₁₅NO₃ClF₃Calculated: C, 58.62; H, 3.69; N, 3.40. Found: C, 58.83; H, 3.71; N,3.22. ¹H-NMR(CDCl₃) δ: 0.93 (3H, t, J=7.2 Hz), 3.60 (3H, s), 4.05 (2H,q, J=7.2 Hz), 7.09 (1H, d, J=2.0 Hz)., 7.46 (2H, d, J=7.8 Hz), 7.50 (1H,dd, J=2.0, 8.4 Hz), 7.75 (2H, d, J=7.8 Hz), 8.46 (1H, d, J=8.4 Hz).

(2)6-Chloro-2-methyl-1-oxo-4-(4-trifluoromethylphenyl)-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 285–28.6° C. Elemental analysis for C₁₈H₁₁NO₃ClF₃Calculated: C, 56.63; H, 2.90; N, 3.67. Found: C, 56.73; H, 2.68; N,3.49. ¹H-NMR(DMSO-d₆) δ: 3.53 (3H, s), 6.99 (1H, d, J2.2 Hz), 7.60 (2H,d, J=8.0 Hz), 7.65 (1H, dd, J=2.2, 8.4 Hz), 7.89 (2H, d, J=,8.34 (1H, d,J=8.4 Hz).

(3)6-Chloro-3-hydroxymethyl-2-methyl-4-(4-trifluoromethylphenyl)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 219–220° C. Elemental analysis for C₁₈H₁₃NO₂ClF₃Calculated: C, 58.79; H, 3.56; N, 3.81. Found: C, 58.94; H, 3.52; N,3.65. ¹H-NMR(CDCl₃) δ: 2.13 (1H, bs) 3.82 (3H, s), 4.43. (2H, d, j=5 0Hz), 7.40 (1H, dd, J=2.0, 8.6 Hz), 7.47 (2H, d, J=7.9 Hz), 7.80 (2H, d,J=7.9 Hz), 8.37 (1H, d, J8.6 Hz).

(4)6-Chloro-3-chloromethyl-2-methyl-4-(4-trifluoromethylphenyl)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example-4 (5))

¹H-NMR(CDCl₃) δ: 3.83 (3H, s), 4.33 (2H, s), 6.91 (1H, d, J=1.8 Hz),7.47 (1H, dd, J=1.8, 8.6 Hz), 7.50 (2H, d, J=7.5 Hz), 7.83 (2H, d, J=7.5Hz), 8.45 (1H, d, J=8.6 35 Hz).

(5)2-{(6-Chloro-2-methyl-1-oxo-4-(4-trifluoromethylphenyl)-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 236–237° C. Elemental analysis for C₂₆H₆N₂O₃ClF₃Calculated: C, 62.85; H, 3.25; N, 5.64. Found: C, 62.92; H, 3.07; N,5.52. ¹H-NMR(DMSO-d₆) δ: 3.62 (3H, s), 4.76 (2H, s), 6.73 (1H, d, J=1.8Hz), 7.54 (2H, d, J=7.6 Hz), 7.58 (1H, dd, J=1.8, 8.4 Hz), 7.73–7.84(6H, m), 8.32(1H, d, J=8.4 Hz).

(6)Tert-butyl{6-chloro-2-methyl-1-oxo-4-(4-trifluoromethylphenyl)-1,2-dihydro-3-isoquinolinyl}-methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 193–194° C. Elemental analysis for C₂₃H₂₂N₂O₃ClF₃Calculated: C, 59.17; H, 4.75; N, 6.00. Found: C, 59.35; H, 4.76; N,5.92. ¹H-NMR(CDCl₃) δ: 1.43 (9H, s), 3.70 (3H, s), 4.16 (2H, d, J=5.8Hz), 4.67 (1H, bs), 6.82 (1H, d, J=2.0 Hz), 7.39(1H, dd, J=2.0, 8.6 Hz),7.42 (2H, d, J=7.9 Hz), 7.81 (2H, d, J=7.9 Hz), 8.36 (1H;, d, J=8.6 Hz).

(7)3-(Aminomethyl)-6-chloro-2-methyl-4-(4-trifluoromethylphenyl)-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 261–262° C. Elemental analysis for C₁₈H₁₅N₂OCl₂F₃ ½H₂OCalculated: C, 52.44; H, 3.91; N, 6.80. Found: C, 52.57; H, 4.09; N,7.02. ¹H-NMR(DMSO-d₆) δ: 3.71 (3H, s), 3.90(2H, s), 6.79 (1H, d, J=2.0Hz), 7.64 (1H, dd, J=2.0, 8.8 Hz), 7.65 (2H, d, J=8.2 Hz), 7.96 (2H, d,J=8.2 Hz), 8.35 (1H, d, J=8.8 Hz), 8.70 (3H, bs).

Example 223-(Aminomethyl)-6,7-dichloro-2-methyl-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) ethyl6,7-dichloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 4 (1))

Melting point 127–128° C. Elemental analysis for C₁₃H₁₁NO₄Cl₂Calculated: C, 49.39; H, 3.51; N, 4.43. Found: C, 49.31; H, 3.50; N,4.36. ¹H-NMR;(CDCl₃) δ: 1.47 (3H, t, J=7.2 Hz), 3.68 (3H, s), 4.51 (2H,q, J=7.2 Hz), 8.21, (1H, s), 8.51 (1H, bs), 11.17 (1H, s).

(2) Ethyl6,7-dichloro-2-methyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 12 (1))

¹H-NMR(CDCl₃) δ: 1.45 (3H, t, J=7.2 Hz), 3.60 (3H, s), 4.49 (2H, q,J=7.2 Hz), 7.86 (1H, s), 8.53.(1H, s).

(3) Ethyl6,7-dichloro-2-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 12 (2))

Melting point 288–289° C. Elemental analysis for C₁₉H₁₅NO₃Cl₂Calculated: C, 60.65; H, 4.02; N, 3.72. Found: C, 60.96; H, 4.04; N,3.62. ¹H-NMR(CDCl₃) δ: 0.92 (3H, t, J=7.2 Hz), 3.60 (3H, s), 4.02 (2H,q, J=7.2 Hz), 7.28–7.32 (3H, m), 7.45–7.48 (3H, m), 8.57 (1H, s).

(4)6,7-Dichloro-2-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 261–262° C. ¹H-NMR(CDCl₃) δ: 3.68 (3H, s), 7.13 (1H, d,J=8.8 Hz), 7.32–7.51.(6H, m), 8.45 (1H, d, J=2.2 Hz).

(5) 6,7-Dichloro-3-hydroxymethyl-2-methyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 211–212° C. Elemental analysis for C₁₇H₁₃NO₂Cl₂Calculated: C, 61.10;H, 3.92;N, 4.19. Found: C, 61.21; H, 3.80; N, 4.12.¹H-NMR(CDCl₃) δ: 2.22 (1H, t, J=5.8 Hz), 3.81 (3H, s), 4.45 (2H, d,J=5.8 Hz), 7.09 (1H, s), 7.27–7.33, (2H, m), 7.48–7.56 (3H, m), 8.47(1H, s).

(6) 6,7-Dichloro-3-chloromethyl-2-methyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.82 (3H, s), 4.36 (2H, s), 7.11 (1H, s), 7.31–7.34(2H, m), 7.49–7.56 (3H, m), 8.57 (1H, s).

(7)2-{(6,7-Dichloro-2-methyl-1oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methyl}-1-isoindole-1,2-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 234–235° C. Elemental analysis for C₂₅H₁₆N₂O₃Cl₂Calculated: C, 64.81; H, 3.48; N, 6.05. Found: C, 64.68; H, 3.56; N,5.86. ¹H-NMR(DMSO-d₆) δ: 3.61 (3H, s), 4.76 (2H, s), 6.94 (1H, s),7.28–7.32 (2H, m), 7.41–7.48 (3H, m), 8.40 (1H, s).

(8)Tert-butyl{6,7-dichloro-2-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(Synthesized according to the method similar to that in Example 1 (6))

Melting point 226–227° C. Elemental analysis for C₂₂H₂₂N₂O₃Cl₂Calculated: C, 60.98; H, 5.12; N, 6.46. Found: C, 61.10; H, 5.30; N,6.37. ¹H-NMR(CDCl₃) δ: 1.43 (9H, s), 3.70 (3H, s), 4.19 (2H, d, J=5.4,Hz), 4.77 (1H, bs), 7.02 (1H, s), 7.22–7.27 (2H, m), 7.49–7.53 (3H, m),8.47 (1H, s).

(9) 3-(Aminomethyl)-6,7-dichloro-2-methyl-4-phenyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 4 (7))

Melting point 266–267° C. Elemental analysis for C₁₇H₁₅N₂OCl₃Calculated: C, 55.23; H, 4.09; N, 7.58. Found: C, 55.40; H, 4.21; N,7.33. ¹H-NMR(DMSO-d₆) δ: 3.72. (3H, s), 3.93 (2H, bs), 6.99 (1H, s),7.39–7.44. (2H, m), 7.55–7.64 (3H, m), 8.43 (1H, s), 8.73 (3H, bs).

Example 233-(Aminomethyl)-6-chloro-2-methyl-4-(3-nitrophenyl)-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-2-methyl-1-oxo-4-(3-nitrophenyl)-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 12 (2))

Melting point 211–212° C. Elemental analysis for C₁₉H₁₅N₂O₅ClCalculated: C, 59.00; H, 3.91; N, 7.24. Found: C, 59.13; H, 3.86; N,7.32. ¹H-NMR(CDCl₃) δ: 1.02 (3H, t, J=7.2 Hz), 3.61 (3H, s), 4.09. (2H,q, J=7.2 Hz), 7.02 (1H, d, J=2.0 Hz), 7.52 (1H, dd, J=2.0, 8.6 Hz),7.68–7.71 (2H, m), 8.23–8.25 (1H, m), 8.32–8.38 (1H, m), 8.47 (1H, d,J=8.6 Hz),

(2)6-Chloro-2-methyl-1-oxo-4-(3-nitrophenyl)-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4

Melting point 259–260° C. ¹H-NMR(CDCl₃) δ: 3.54 (3H, s), 7.04 (1H, d,J=2.0 Hz), 7.65 (1H, dd, J=2.0, 8.6 Hz), 7.82–7.85 (2H, m), 8.19–8.21(1H, m), 8.33–8.39 (2H, m).

(3)6-Chloro-3-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 227–228° C. Elemental analysis for C₁₇H₁₃N₂O₄Cl ½H₂OCalculated: C, 57.72; H, 3.99; N, 7.92. Found: C, 57.96; H, 3.88; N,7.63. ¹H-NMR(CDCl₃) δ: 3.85 (3H, s), 4.34 (2H, d, J=3.2 Hz), 4.80 (1H,bs), 6.86 (1H, d, J=2.0 Hz), 7.42 (1H, dd, J=2.0, 8.6 Hz), 7.69–7.73(2H, m), 8.27–8.38 (2H, m), 8.43 (1H, d, J=8.6 Hz).

(4)6-Chloro-3-chloromethyl-2-methyl-4-(3-nitrophenyl)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 3.84 (3H, s), 4.32 (2H, s), 6.86 (1H, d, J=2.0 Hz),7.49 (1H, dd, J=2.0, 8.6 Hz), 7.73–7.79 (2H, m), 8.25–8.26 (1H, m),8.39–8.43 (1H, m), 8.46 (1H, d, J=8.6 Hz).

(5)2-{(6-Chloro-2-methyl-1-oxo-4-(3-nitrophenyl)-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 246–247° C. Elemental analysis for C₂₅H₁₆N₃O₅ClCalculated: C, 63.37; H, 3.40; N, 8.87. Found C, 63.14; H, 3.33; N,8.50. ¹H-NMR(DMSO-d₆) δ: 3.65 (3H, s), 4.71 (1H, d, J=16.3 Hz), 4.80(1H, d, J=16.3 Hz) 6.79 (1H, d, J=2.0 Hz), 7.59 (1H, d, J=2.0, 8.6 Hz),7.69–7.84 (5H, m), 8.13–8.14 (1H, m), 8.23–8.29.(4H, m),8.33 (1H, d,J=8.6 Hz).

(6)Tert-butyl{6-chloro-2-methyl-1-oxo-4-(3-nitrophenyl)-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the, method similar to that in Example 1 (6))

Melting point 231–232° C. Elemental analysis for C₂₂H₂₂N₃O₅ClCalculated: C, 59.53; H, 5.00; N, 9.47. Found: C, 59.51; H, 5.01; N,9.25. ¹H-NMR(CDCl₃) δ: 1.42 (9H, s), 3.71 (3H, s), 4.14–4.17 (2H, m),4.81 (1H, bs), 6.77 (1H, s), 7.18–7.23 (1H, m), 7.62 (1H, d, J=7.8 Hz),7.76 (1H, t, J=7.8 Hz), 8.17 (1H, s), 8.36–8.42 (2H, m).

(7)3-(Aminomethyl)-6-chloro-2-methyl-4-(3-nitrophenyl)-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 263–264° C. Elemental analysis for C₁₇H₁₅N₃O₃Cl₂Calculated: C, 53.70; H, 3.98; N, 11.05. Found: C, 53.56; H, 4.09; N,10.95. ¹H-NMR(DMSO-d₆) δ: 3.71 (3H, s), 3.83–3.93 (2H, m), 36.86 (1H, d,J=2.0 Hz), 7.65 (1H, dd, J=2.0, 8.6 Hz), 7.82–7.93 (2H, m), 8.23–8.25(1H, m), 8.35 (1H, d, J=8.6 Hz), 8.39–8.44 (1H, m), 8.66 (3H, bs).

Example 243-(Aminomethyl)-4-(3-aminophenyl)-6-chloro-2-methyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl{6-chloro-2-methyl-1-oxo-4-(3-nitrophenyl)-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 23 (6))(0.89 g, 2 mmol) was added to an aqueous solution (10 ml) of potassiumcarbonate (2.90 g, 21 mmol) and sodium hydrosulfite (2.44 g, 14 mmol)and the mixture was stirred at room temperature for 1 h. The reactionmixture was poured into water and extracted with ethyl acetate. Afterwashing the extract with water, the extract was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl{4-(3-aminophenyl)-6-chloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.48 g, 58.5%) as crystals.

Melting point 157–158° C. ¹H-NMR(CDCl₃) δ: 1.43 (9H, s), 3.69 (3H, s),4.22 (2H, d, J=5.6 Hz), 4.65 (1H, bs), 6.54–6.62 (1H, m), 6.76–6.83 (1H,m), 6.90–7.03 (1H, m), 7.08 (1H, dd, J=2.0, 8.0 Hz), 7.34–7.45 (2H, m),8.35 (1H, d, J=8.0 Hz).

(2)3-(Aminomethyl)-4-(3-aminophenyl)-6-chloro-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 255° C. Elemental analysis for C₁₇H₁₈N₃OCl₃ ½H₂OCalculated: C, 51.60; H, 4.84; N, 10.62. Found: C, 51.76; H, 4.64; N,10.29. ¹H-NMR(DMSO-d₆) δ: 3.70 (3H, s), 3.91 (2H,bs), 6.87–6.93 (2H,m),7.38–7.46 (1H, m), 7.57–7.75 (3H, m), 8.35(1H, d, J=8.8 Hz), 8.73–8.87(6H, m).

Example 253-(Aminomethyl)-4-butoxy-6-chloro-2-propyl-1-(2H)-isoquinolinonehydrochloride

(1) Ethyl6-chloro-4-hydroxy-1-oxo-2-propyl-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 61–62° C. Elemental analysis for C₁₅H₁₆NO₄Cl Calculated:C, 58.16; H, 5.21; N, 4.52. Found: C, 58.22; H, 5.28; N, 4.45.¹H-NMR(CDCl₃) δ: 0.93 (3H, t, J=7.3 Hz), 1.47 (3H, t, J=7.2 Hz),1.69–1.84 (2H, m), 4.17–4.24 (2H, m), 4.51 (2H, q, J=7.2 Hz), 7.62 (1H,dd, J=2.2, 8.6 Hz), 8.11 (1H, d, J=2.2 Hz), 8.37 (1H, d, J=2.2 Hz),11.28 (1H, s).

(2) Ethyl4-butoxy-6-chloro-1-oxo-2-propyl-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

Melting point 72–73° C. Elemental analysis for C₁₉H₂₄NO₄Cl Calculated:C, 62.38; H, 6.61; N, 3.83. Found: C, 62.32; H, 6.55; N, 3.56.¹H-NMR(CDCl₃) δ: 0.94 (3H, t, J=7.3 Hz), 1.01 (3H, t, J=7.3 Hz), 1.43(3H, t, J=7–1 Hz), 1.48–1.62 (2H, m), 1.68–1.86 (4H, m), 3.85–3.98 (4H,m), 4.47 (2H, q, J=7.1 Hz), 7.49 (1H, dd, J=2.0, 8.7 Hz), 7.69 (1H, d,J=2.0 Hz), 8.37 (1H, d, J=8.7 Hz).

(3)4-Butoxy-6-chloro-1-oxo-2-propyl-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 175–176° C. Elemental analysis for C₁₇H₂₀NO₄Cl Calculated:C, 60.45; H, 5.97; N, 4.15. Found: C, 60.45; H, 6.27; N, 3.98.¹H-NMR(CDCl₃) δ: 0.91–1.06 (6H, m), 1.50–1.65 (2H, m), 1.80–1.85 (4H,m), 3.95–4.04 (4H, m), 7.46 (1H, dd, J=2.0, 8.6 Hz), 7.70 (1H, d, J=2.0Hz), 8.36 (1H, d, J8.6 Hz).

(4) 4-Butoxy-6-chloro-3-hydroxymethyl-2-propyl-1 (2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 108–109° C. Elemental analysis for C₁₇H₂₂NO₃Cl Calculated:C, 63.06; H, 6.85; N, 4.33. Found: C, 62.75; H, 6.89; N, 4.12.¹H-NMR(CDCl₃) δ: 1.00(3H, t, J=7.6 Hz), 1.04 (3H, t, J=7.0 Hz),1.49–1.92 (6H, m), 2.43 (2H, t, J=6.6 Hz), 4.79 (1H, t, J=5.6 Hz), 3.87(2H, t, J=6.6 Hz), 4.12–4.20 (2H, m), 4.79 (2H, d, J=5.6 Hz), 7.41 (1H,dd, J=2.0, 8.6 Hz), 7.61 (1H, d, J=2.0 Hz), 8.29(1H, d, J=8.6 Hz).

(5) 4-Butoxy-6-chloro-3-chloromethyl-2-propyl-1(2H)isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.02 (3H, t, J=7.4 Hz), 1.05 (3H, t, J=7.2 Hz),1.56–1.97 (6H, m), 3.99 (2H, t, J=6–5 Hz), 4.11–4.19 (2H, m), 4.78 (2H,s), 7.47 (1H, dd, J=2.2, 8.6 Hz), 7.70 (1H, d, J=2.2 Hz), 8.37 (1H, d,J=8.6 Hz).

(6)2-{(4-Butoxy-6-chloro-1-oxo-2-propyl-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 153–154° C. Elemental analysis for C₂₅H₂₅N₂O₄ClCalculated: C, 66.29; H, 5.56; N, 6.18. Found: C, 66.31; H, 5.48; N,6.08. ¹H-NMR(DMSO-d₆) δ: 0.80 (3H, t, J=7.3 Hz), 0.92 (3H, t, J=7.4 Hz),1.38–1.58 (4H, m), 1.69–1.82 (2H, m), 3.89–4.02 (4H, m), 5.02 (2H, s),7.59, (H, dd, J=2.0, 8.6 Hz), 7.65 (1H, d, J=2.0 Hz), 7.83–7.92 (4H, m),8.24 (1H, d, J=8.6 Hz).

(7)Tert-butyl(4-butoxy-6-chloro-1-oxo-2-propyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 120–121° C. Elemental analysis for C₂₂H₃₁N₂O₄ClCalculated: C, 62.48; H, 7.39; N, 6.62. Found: C, 62.53; H, 7.40; N,6.49. ¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.4 Hz), 1.04 (3H, t, J=6.8 Hz),1.47 (9H, s), 1.52–1.90 (4H, m), 3.84 (2H, t, J=6.6 Hz), 4.01–4.08 (2H,m), 4.50 (2H, d, J=5.6 Hz), 4.77 (1H, bs), 7.43 (1H, dd, J=2.0, 8.6 Hz),7.64, (1H, d, J=2.0 Hz), 8.34 (1H, d, J=8.6 Hz).

(8) 3-(Aminomethyl)-4-butoxy-6-chloro-2-propyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 124–125° C. Elemental analysis for C₁₇H₂₄N₂O₂Cl₂ ¼H₂OCalculated: C, 56.13; H, 6.79; N, 7.70. Found: C, 56.15; H, 6.82; N,7.53. ¹H-NMR(DMSO-d₆) δ: 0.95 (3H, t, J7.4 Hz), 1.00 (3H, t, J=7.3 Hz),1.46–1.68 (4H, m), 1.78–1.92 (2H, m), 3.93 (2H, t, J=6.6 Hz), 3.93–4.02(2H, m), 4.16 (2H, s), 7.66 (1H, dd, J=2.0, 8.4 Hz), 7.72 (1H, d, J=2.0Hz), 8.28 (1H, d, J=8.4 Hz), 8.75 (3H, bs).

Example 263-(Aminomethyl)-4-butoxy-6,7-dichloro-2-isobutyl-1(2H)isoquinolinonehydrochloride

(1) Ethyl6,7-dichloro-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 111–112° C. Elemental analysis is for C₁₆H₁₇NO₄Cl₂Calculated: C, 53.65; H, 4.78; N, 3.91. Found: C, 53.62; H, 4.65;N,3.66. ¹H-NMR(CDCl₃) δ: 0.82 (6H, d, J=6.6 Hz), 1.46 (3H, t, J=7.2 Hz),1.73–1.87 (1H, m), 4.38 (2H, d, J=7.8 Hz), 4.50 (2H, q, J=7.2 Hz), 8.23(1H, s), 8.53 (1H, s), 11.16 (1H, s).

(2) Ethyl4-butoxy-6,7-dichloro-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.90 (6H, d, J=6.8 Hz), 1.01 (3H, t, J=7.4 Hz), 1.44(3H, t, J=7.1 Hz), 1.48–1.62 (2H, m), 1.72–1.8.5 (2H, m), 2.05–2.17 (1H,m), 3.88 (2H, d, J=7.6 Hz), 3.94 (2H, t, J=6.5 Hz), 4–46 (2H, q, J=7.1Hz), 7.81 (1H, s), 8.51 (1H, s).

(3)4-Butoxy-6,7-dichloro-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 104–105° C. Elemental analysis for C₁₈H₂₁NO₄Cl₂Calculated: C, 55.97; H, 5.48; N, 3.63. Found: C, 55.82; H, 5.43; N,3.46. ¹H-NMR(CDCl₃) δ: 0.91 (6H, d, J=6.6 Hz), 1.00 (3H, t, J=7.3 Hz),1.45–1.64 (2H, m), 1.75–1.86 (2H, m), 2.08–2.22 (1H, m), 3.97–4.05 (4H,m), 7.65 (1H, s), 8.45 (1H, s).

(4)4-Butoxy-6,7-dichloro-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 99–100° C. Elemental analysis for C₁₈H₂₃NO₃Cl₂ Calculated:C, 58.07; H, 6.23; N, 3.76. Found: C, 57.90; H, 6.09; N, 3.46.¹H-NMR(CDCl₃) δ: 0.92 (6H, d, J=6.6 Hz), 1.05 (3H, t, J=7.3 Hz),1.50–1.69 (2H, m), 1.80–1.94 (2H, m), 2.04–2.21 (1H, m), 2.57 (1H, bs),3.88 (2H, t, J=6.6 Hz), 4.09 (2H, d, J=7.8 Hz), 4.79 (2H, d, J=4.8 Hz),7.69 (1H, d, J=2.0 Hz), 8.35 (1H, d, J=2.0 Hz).

(5) 4-Butoxy-3-chloromethyl-6,7-dichloro-2-isobutyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=7.0 Hz), 1.05 (3H, t, J=7.3 Hz),1.51–1.66 (2H, m), 1.82–1.96 (2H, m), 2.04–2.21 (1H, m), 3.97 (2H, t,J=6.5 Hz), 4.06 (2H, d, J=5.8 Hz), 4.77(2H, s), 7.81 (1H, s), 8.50 (1H,s).

(6))2-{(4-Butoxy-6,7-dichloro-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 103–104° C. Elemental analysis for C₂₆H₂₆N₂O₄Cl₂Calculated: C, 62.28; H, 5.23; N, 5.59. Found: C, 62.18; H, 5.03; N,5.53. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.00 (3H, t, J=7.4 Hz),1.43–1.58 (2H, m), 1.79–1.92 (2H, m), 2.07–2.21 (1H, m), 3.94–4.04 (4H,m), 5.01 (2H, s), 7.7.0–7.90 (5H, m), 8.49 (1H s).

(7)Tert-butyl(4-butoxy-6,7-dichloro-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 138–139° C. Elemental analysis for C₂₃H₃₂N₂O₄Cl₂Calculated: C, 58.85; H, 6.44; N, 5.97. Found: C, 58.60; H, 6.64; N,5.72. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.3 Hz),1.47 (9H, s), 1.47–1.67 (2H, m), 1.79–1.93 (2H, m), 2.07–2.21 (1H, m),3.84 (2H, t, J=6.5 Hz), 3.98 (2H, d, J=7.4 Hz), 4.49 (2H, d, J=5.4 Hz),4.80 (1H, bs), 7.75 (1H, s), 8.45 (1H, s).

(8) 3-(Aminomethyl)-4-butoxy-6,7-dichloro-2-isobutyl-1(2H)-isoquinolinehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 168–170° C. Elemental analysis for C₁₈H₂₅N₂O₂Cl₃Calculated: C, 53.02; H, 6.18; N, 6.87. Found: C, 53.28; H, 6.13; N,6.76. ¹H-NMR(DMSO-d₆) δ: 0.88 (6H, d, J=6.6 Hz), 1.00 (3H, t, J=7.1 Hz),1.45–1.63 (2H, m), 1.78–1.96 (2H, i), 1.99–2.09 (1H, m), 3.91–3.99 (4H,m), 4.17 (2H, s), 7.92 (1H, s), 8.38 (1H, s), 8.68 (3H, bs).

Example 273-(Aminomethyl)-4-butoxy-6,7-dichloro-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6,7-dichloro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 117–118° C. Elemental analysis for C₁₇H₁₉NO₄Cl₂Calculated: C, 54.85; H, 5.14; N, 3.76. Found: C, 54.89; H, 5.14; N,3.62. ¹H-NMR(CDCl₃) δ: 0.84 (9H, s), 1.47 (3H, t, J=7.1 Hz), 4.49 (2H,q, J=7.1 Hz), 4.51 (2H, bs), 8.22 (1H, s), 8.52 (1H, s), 10.73 (1H, s).

(2) Ethyl4-butoxy-6,7-dichloro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.93 (9H, s), 1.02 (3H, t, J=7.3 Hz), 1.44 (3H, t,J=7.1 Hz), 1.48–1.59 (2H, m), 1.73–83 (2H, m), 3.94 (2H, t, J=6.6 Hz),4.07 (2H, bs), 4.43 (2H, q, J=7.1 Hz), 7.83 (1H, s), 8.51 (1H, s).

(3)4-Butoxy-6,7-dichloro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 138–139° C. Elemental analysis for Cl₁₉H₂₃NO₄Cl₂Calculated: C, 57.01; H, 5.79; N, 3.50. Found: C, 57.03; H 5.86; N,3.30. ¹H-NMR(CDCl₃) δ: 0.93 (9H, s), 1.01 (3H, t, J=7.1 Hz), 1.40–1.64(2H, m), 1.77–1.91 (2H, m), 4.00 (2H, t, J=6.6 Hz), 4.23 (2H, bs), 5.81(1H, bs), 7.77 (1H, s), 8.45

(4)4-Butoxy-6,7-dichloro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 178–179° C. Elemental analysis for Cl₁₉H₂₅NO₃Cl ₂Calculated: C, 59.07; H, 6.52; N, 3.63. Found: C, 59.00 H, 6.39; N,3.33. ¹H-NMR(CDCl₃) δ: 0.93 (9H, s), 1.06 (3H, t, J=7.3 Hz), 1.56–1.67(2H, m), 1.81–1.92 (2H, m), 3.08 (1H, t, J=5.9 Hz), 3.90 (2H, t, J=6.4,Hz), 4.20 (2H, bs), 4.84 (2H, bs), 7.66 (1H, s), 8.22 (1H, s).

(5)4-Butoxy-3-chloromethyl-6,7-dichloro-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.05 (3H, t, J7.3 Hz), 1.55–1.70 (2H, m),1.82–1.95. (2H, m), 3.93 (2H, t, J=6.6 Hz), 4.17. (2H, bs), 4.84 (2H,bs), 7.80 (1H, s), 8.50 (1H, s).

(6)2-{(4-Butoxy-6,7-dichloro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 145–146° C. Elemental analysis for C₂₇H₂₈N₂O₄Cl₂Calculated: C, 62.92; H, 5.48; N, 5.43. Found: C, 62.76; H, 5.76; N,5.22. ¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.01 (3H, t, J=7.1 Hz), 1.49–1.61(2H, m), 1.81–1.95 (2H, m), 4.00 (2H, t, J=6.8 Hz), 4.07 (2H, bs), 5.05(,2H, s), 7.70–7.86 (5H, m), 8.47 (1H, s).

(7)Tert-butyl(4-butoxy-6,7-dichloro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 152–153° C. Elemental analysis for C₂₄H₃₄N₂O₄Cl₂Calculated: C, 59.39; H, 7.06; N, 5.77. Found: C, 59.15; H, 7.10; N,5.54. ¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.01 (3H, t, J=7.0 Hz), 1.46 (9H,s), 1.53–1.68 (2H, m), 1.80–1.94 (2H, m), 3.85 (2H, t, J=6.6 Hz),4.11–4.28 (2H, m), 4.55 (2H, d, J=5.4 Hz), 4.83 (1H, bs), 7.74 (1H, d,J=1.7 Hz), 8.41 (1H, d, J=1.7 Hz).

(3-(Aminomethyl)-4-butoxy-6,7-dichloro-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 157–158° C. Elemental analysis for C₁₉H₂N₂O₂Cl₃ ½H₂OCalculated: C, 52.97; H, 6.55; N, 6.50. Found: C, 53.04; H, 6.59; N,6.46. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 0.99 (3H, t, J=7.1 Hz), 1.45–1.60(2H, m), 1.77–1.91 (2H, m), 3.95 (2H, t, J=6.4 Hz), 4.11 (2H, bs), 4.24(2H, bs), 7.92 (1H, s), 8.38 (1H, s), 8.62 (3H, bs).

Example 28 3-(Aminomethyl)-2-benzyl-4-butoxy-6,7-dichloro-1(2H)isoquinolinone hydrochloride

(1) Ethyl2-benzyl-6,7-dichloro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 140–141° C. Elemental analysis for C₁₉H₁₅NO₄Cl₂Calculated:C, 58.18; H, 3.85; N, 3.57.Found: C, 58.22; H, 3.98; N, 3.27.¹H-NMR(CDCl₃) δ: 1.18 (3H, t, J=7.2 Hz), 4.28 (2H, q, J=7.2 Hz), 5.60(2H, s), 7.03–7.07 (2H, m), 7.20–7.32 (3H, m), 8.26 (1H, s), 8.57 (1H,s), 11.20 (1H, s).

(2) Ethyl2-benzyl-4-butoxy-6,7-dichloro-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.98 (3H, t, J=7.3 Hz), 1.13 (3H, t, J=7.2 Hz),1.40–1.59 (2H, m), 1.70–1.83 (2H, m), 3.92 (2H, t, J=6.4 Hz), 4.17 (2H,q, J=7.2 Hz), 5.34 (2H, s), 7.16–7.31 (5H, m), 7.83. (1H, s), 8.56 (1H,s).

(3)2-Benzyl-4-butoxy-6,7-dichloro-1-oxo-1,2-dihydro-3isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 128–129° C. Elemental analysis for C₂₁H₁₉NO₄Cl₂Calculated: C, 60.01; H, 4.59; N, 3.33. Found: C, 60.00; H, 4.40; N,3.11. ¹H-NMR(CDCl₃) δ: 0.97 (3H, t, J=7.3 Hz), 1.41–1.60 (2H, m),1.72–1.86 (2H, m), 3.97 (2H, t, J=6.4 Hz), 4.83 (1H, bs), 5.42 (2H, s),7.18–7.26 (5H, m), 7.83 (.1H, s), 8.53 (1H, s).

(4) 2-Benzyl-4-butoxy-6,7-dichloro-3-hydroxymethyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 110–111° C. Elemental analysis for C₂₁H₂NO₃Cl₂ Calculated:C, 62.08; H, 5.21; N, 3.45. Found: C, 62.01; H, 5.28; N, 3.25.¹H-NMR(CDCl₃) δ: 1.02 (3H, t, J=7.1 Hz), 1.47–1.65 (2H, m), 1.77–1.91(2H, m), 2.23 (1H, bs), 3.87 (2H, t, J=6.6 Hz), 4.65 (2H, d, J=5.6 Hz),5.9 (2H, s), 7.12–7.16 (2H, m), 7.25–7.34(3H, m), 7.78 (1H, d, J=1.7Hz), 8.50 (1H, d, J=1.7 Hz).

(5) 2-Benzyl-4-butoxy-3-chloromethyl-6,7-dichloro-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.03 (3H, d, J=7.2 Hz), 1.53–1.64 (2H, m), 1.80–1.95(2H, m), 4.00 (2H, t, J=6.4 Hz), 4.60 (2H, s), 5.60 (2H, s), 7.10–7.34(5H, m), 7.85 (11H, s), 8.58 (1H, s).

(6)2-{(2-Benzyl-4-butoxy-6,7-dichloro-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 161–162° C. Elemental analysis for C₂₉H₂₈N₂O₄Cl₂Calculated: C, 65.05; H, 4.52; N, 5.23. Found: C, 64.98; H, 4.64; N,5.07. ¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.3, Hz), 1.47–1.65. (2H, m),1.80–1.94 (2H, m), 4.12 (2H, t, J=6.7 Hz), 5.02 (2H, s), 5.37 (2H, s),6.65–6.72 (1H, m), 6.78–6.92 (4H, m), 7.51–7.60 (4H, m), 7.90 (1H, s),8.53 (1H, s).

(7)Tert-butyl(2-benzyl-4-butoxy-6,7-dichloro-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 151–152° C. Elemental analysis for C₂₆H₃₀N₂O₄Cl₂Calculated: C, 61.78; H, 5.98; N, 5.54. Found: C, 61.73; H, 6.17; N,5.45. ¹H-NMR(CDCl₃) δ: 1.02 (3H, t, J=7.3 Hz), 1.42 (9H, s), 1.47–1.60(2H, m), 1.76–1.87 (2H, m), 3.83 (2H, t, J=6.6. Hz), 4.38 (2H, d, J=6.0Hz), 4.74 (1H, bs), 5.45 (2H, s), 7.19–7.35 (5H, m), 7.78(1H, s), 8.53(1H, s).

(8) 3-(Aminomethyl)-2-benzyl-4-butoxy-6,7-dichloro-1(2H)-isoquinolinehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 191–192° C. Elemental analysis for C₂₁H₂₃N₂O₂Cl₃Calculated: C, 57.09; H, 5.25; N, 6.34. Found: C, 56.77; H, 5.14; N,6.04. ¹H-NMR(DMSO-d₆) δ: 0.97 (3H, t, J=7.3 Hz), 1.43–1.59 (2H, m),1.76–1.90 (2H, m), 3.91–3.98 (4H, m), 5.47 (2H, s), 7.18–7.22 (2H, m),7.28–7.39 (3H, m), 7.96 (1H, s), 8.43 (1H, s), 8.89 (3H, bs).

Example 293-(Aminomethyl)-6,7-dichloro-2-isobutyl-4-pentyloxy-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6,7-dichloro-2-isobutyl-1-oxo-4-pentyloxy-1,2-dihydro-3-isoquinolinecarboxylatesynthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.90 (6H, d, J=6.6 Hz), 0.96 (3H, t, J=6.6 Hz),1.29–1.54 (7H, m), 1.74–1.87 (2H, m), 2.05–2.17 (1H, m), 3.90 (2H, d,J=5.8 Hz), 3.93 (2H, t, J=6.6 Hz), 4.46 (2H, q, J=7.1 Hz), 7.81 (1H, s),8.51 (1H, s).

(2)6,7-Dichloro-2-isobutyl-1-oxo-4-pentyloxy-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 124–125° C. Elemental analysis for Cl₁₉H₂₃NO₄Cl₂Calculated: C, 57.01; H, 5.79; N, 3.50. Found: C, 57.13; H, 5.72 N,3.40. ¹H-NMR(CDCl₃) δ: 0.90 (6H, d, J=6.6 Hz), 0.95 (3H, t, J=6.6 Hz),1.31–1.57 (4H, m), 1.7–1.91 (2H, m), 2.07–2.21 (1H, m), 3.95–4.04 (4H,m), 4.35 (1H, bs), 7.75 (1H, s), 8.45 (1H, s).

(3)6,7-Dichloro-3-hydroxymethyl-2-isobutyl-4-pentyloxy-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 86–87° C. Elemental analysis for C₁₉H₂₅NO₃Cl₂ Calculated:C, 59.07; H, 6.52; N, 3.63. Found: C, 58.91; H, 6.65; N, 3.48.¹H-NMR(CDCl₃) δ: 0.82 (6H, d, J=6.6 Hz), 0.99 (3H, t, J=7.0 Hz),1.39–1.59 (4H, m), 1.82–1.92 (2H, m), 2.07–2.17 (1H, m), 2.67 (1H, bs),3.87 (2H, t, J=6.4 Hz), 4.09 (2H, d, J=7.6 Hz), 4.78 (2H, d, J=4.8 Hz),7.69 (1H, s), 8.35 (1H, s).

(4)3-Chloromethyl-6,7-dichloro-2-isobutyl-4–4pentyloxy-1(2H)-isoquinoline(synthesized according to the method similar to that in Example 4,(5))

¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 0.99 (3H, t, J=7.0 Hz),1.36–1.61 (4H, m), 1.84–1.98 (2H, m), 2.05–2.22 (1H, m), 3.96 (2H, t,J=6.4 Hz), 4.07 (2H, d, J=7.6 Hz), 4.78 (2H, s), 7.81 (1H, s), 8.51 (1H,s).

(5)2-{(6,7-Dichloro-2-isobutyl-1-oxo-4-pentyloxy-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 119–120° C. Elemental analysis for C₂₇H₂₈N₂O₄Cl₂Calculated: C, 62.92; H, 5.48; N, 5.43. Found: C, 62.95; H, 5.43; N,5.55. ¹H-NMR(CDCl₃) δ: 0.88–1.04 (9H, m), 1.30–1.54 (4H, m), 1.80–1.90(2H, m), 2.05–2.17 (1H, m), 3.90–4.05 (4H, m), 5.06 (2H, s), 7.70–7.89(5H, m), 8.49 (1H, s).

(6)Tert-butyl(6,7-dichloro-2-isobutyl-1-oxo-4-pentyloxy-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 113–114° C. Elemental analysis for C₂₄H₃₄N₂O₄Cl₂Calculated: C, 59.39; H, 7.06; N, 5.77. Found: C, 59.39; H, 7.00; N,5.67. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 0.98 (3H, t, J=7.1 Hz),1.38–1.57 (13H, m), 1.81–1.95 (2H, m), 2.07–2.21 (1H, m), 3.84 (2H, t,J=6.6 Hz), 3.97 (2H, d, J=7.4 Hz), 4.49 (2H, d, J=5.4 Hz), 4.81 (1H,bs), 7.75 (1H, s), 8.46 (1H, s).

(7)3-(Aminomethyl)-6,7-dichloro-2-isobutyl-4-pentyloxy-1(2H)-isoquinolinone,hydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 167–169° C. Elemental analysis for C₁₉H₂₇N₂O₂Cl₃Calculated: C, 54.10; H, 6.45; N, 6.64. Found: C, 54.09; H, 6.45; N,6.54. ¹H-NMR(DMSO-d₆) δ: 0.88 (6H, d, J=7.0 Hz), 0.95,(3H, t, J=7.0 Hz),1.31–1.57 (4H, m), 1.80–2.10 (3H, m), 3.91–3.99 (4H, m), 4.17 (2H, s),7.92 (1H, s), 8.38 (1H, s), 8.72 (3H, bs).

Example 303-(Aminomethyl)-4-butoxy-6,7-dichloro-2-isopropyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6,7-dichloro-4-hydroxy-2-isopropyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 124–125° C. Elemental analysis for C₁₅H₁₅NO₄Cl₂½H₂OCalculated: C, 51.01; H, 4.57; N, 3.97. Found: C, 51.23; H, 4.25; N,3.86. ¹H-NMR(CDCl₃) δ: 1.45 (3H, t, J=7.1 Hz), 1.62 (6H, d, J=6.6 Hz),4.19–4.33:(1H, m), 4.47 (2H, q, J=7.17 Hz), 8.17 (1H, s), 8.46 (1H, s),10.64 (1H, s).

(2) Ethyl4-butoxy-6,7-dichloro-2-isopropyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.1 Hz), 1.44 (3H, t, J=7.2 Hz),1.46–1.59 (2H, m), 1.64 (6H, d, J=6.6 Hz), 1.71–1.85 (2H, m), 3.93 (2H,t, J=6.4 Hz), 4.01–4.18 (1H, m), 4.45 (2H, q, J=7.2 Hz), 7.77 (1H, s),8.47 (1H, s).

(3)4-Butoxy-6,7,-dichloro-2-isopropyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 186–187° C. Elemental analysis for C₁₇H₁₉NO₄Cl₂Calculated: C, 54.85; H, 5.14; N, 3.76. Found: C, 54.90; H, 5.12; N,3.68. ¹H-NMR(CDCl₃) δ: 0.99 (3H, t, J=7.3 Hz), 1.44–1.62 (2H, m), 1.68(6H, d, J=6.6 Hz), 1.74–1.88 (2H, m), 4.00 (2H, t, J=6.4 Hz), 4.21–4.34(1H, m), 5.11 (1H, bs), 7.80 (1H, s), 8.51 (1H, s).

(4)4-Butoxy-6,7-dichloro-3-hydroxymethyl-2-isopropyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 150–151° C. Elemental analysis for C₁₇H₂₁NO₃Cl₂ ¼H₂OCalculated: C, 56.29; H, 5.97, N, 3.86. Found: C, 56.53; H, 6.01; N,3.96. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.4 Hz), 1.44–1.66 (2H, m), 1.67(6H, d, J=7.0 Hz), 1.78–1.92 (2H, m), 2.04 (1H, bs), 3.85 (2H, t, J=6.6Hz), 4.64–4.74 (1H, m), 4.81 (2H, s), 7.73 (1H, s), 8.44 (1H, s).

(5)4-Butoxy-3-chloromethyl-6,7-dichloro-2-isopropyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.05 (3H, t, J=7.1 Hz), 1.51–1.66 (2H, m), 1.70 (6H, d,J=6.6 Hz), 1.78–1.95 (2H, m), 3.96 (2H, t, J=6.4 Hz), 4.47–4.60 (1H, m),4.77 (2H, s), 7.77 (1H, s), 8.46 (1H, s). (6)2-[(4-Butoxy-6,7-dichloro-2-isopropyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (synthesized according to the method similar to that inExample 4 (6))

Melting point 185–186° C. Elemental analysis for C₂₅H₂₄N₂O₄Cl₂Calculated: C, 61.61; H, 4.96; N, 5.75. Found: C, 61.71; H, 4.89; N,5.66. ¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.4 Hz), 1.47 (6H, d, J=6.6 Hz),1.48–1.68 (2H, m), 1.80–1.94 (2H, m), 4.05 (2H, t, J=6.6 Hz), 4.19–4.32(1H, m), 5.09 (2H, s), 7.73–7.89 (5H, m), 8.43 (1H, s). (7)Tert-butyl(4-butoxy-6.7-dichloro-2-isopropyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 169.5–170° C. Elemental analysis for C₂₂H₃₀N₂O₄Cl₂Calculated: C, 57.77; H, 6.61; N, 6.12. Found: C, 57.74; H, 6.76; N,6.13. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.4 Hz), 1–47 (9H, s), 1.48–1.62(2H, m), 1.63,(6H, d, J=6.6 Hz), 1.71–1.92 (2H, m), 3.81 (2H, t, J=6–4Hz), 4.41–4.52 (1H, m), 4.53 (2H, d, J=5.4 Hz), 4.67 (1H, bs), 7.73 (1H,s), 8.45 (1H, s).

(8)3-(Aminomethyl)-4-butoxy-6,7-dichloro-2-isopropyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7)

Melting point 264–265° C. Elemental analysis for C₁₇H₂₃N₂O₂Cl₃Calculated: C, 51.86; H, 5.89; N, 7.11. Found: C, 52.00; H, 5.70; N,7.18. ¹H-NMR(DMSO-d₆) δ: 0.99 (3H, t, J=7.1 Hz), 1.45–1.56 (2H, m), 1.57(6H, d, J=6.6 Hz), 1.77–1.91 (2H, m), 3.90 (2H, t, J=6.4 Hz), 4.23 (2H,s), 4.36–4.49 (1H, m), 7.87 (1H, s), 8.34 (1H, s), 8.85 (3H, bs).

Example 313-(Aminomethyl)-4-butoxy-6,7-dichloro-2-cyclopropyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl2-cyclopropyl-6,7-dichloro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1)

Melting point 119.5–120° C. Elemental analysis for C₁₅H₁₃NO₄C₂Calculated: C, 52.63; H, 3.83; N, 4.09. Found: C, 52.97; H, 3.90; N,3.78. ¹H-NMR(CDCl₃) δ: 0.62–0.70 (2H, m), 1.05–1.16 (2H, m), 1.44 (3H,t, J=7.2 Hz), 3.33–3.44 (1H, m), 4.48 (2H, q, J=7.2Hz), 8.16 (1H, s),8.47 (1H, s), 10.58 (1H, s).

(2) Ethyl4-butoxy-6,7-dichloro-2-cyclopropyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in,Example 1 (2))

Melting point 72.5–73.5° C. Elemental analysis for C₁₉H₂₁NO₄Cl₂Calculated: C, 57.30; H, 5.31; N, 3.52. Found: C, 57.24; H, 5.24; N,3.47. ¹H-NMR(CDCl₃) δ: 0.82–0.91 (2H, m), 1.01 (3H, t, J=7.3 Hz),1.01–1.15 (2H, m), 1.44 (3H, t, J=7.2 Hz), 1.43–1.60 (2H, m), 1.72–1.86(2H, m), 3.10–3.22 (1H, m), 3.94 (2H, t, J=6.5 Hz), 4.46 (2H, q, J=7.2Hz), 7.80 (1H, s), 8.47 (1H, s).

(3)4-Butoxy-6,7-dichloro-2-cyclopropyl-1oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4

Melting point 198–201° C. Elemental analysis for C₁₇H₁₇NO₄Cl₂Calculated:C, 55.15; H, 4.68; N, 3.78. Found: C, 55.14; H, 4.47; N, 3.73.¹H-NMR(CDCl₃) δ: 0.85–0.94 (2H, m), 1.00(3H, t, J=7.3 Hz), 1.14–1.30(2H, m), 1.42–1.63 (2H, m), 1.75–1.89 (2H, m), 3.26–3.35 (1H, m), 4.00(2H, t, J=6.4 Hz), 5.55 (1H, bs), 7.75 (1H, s), 8.41 (1H, s).

(4),4-Butoxy-6,7-dichloro-2-cyclopropyl-3-hydroxyethyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 145–146° C. Elemental analysis for C₁₇H₁₉NO₃Cl₂Calculated: C, 57.32; H, 5.38; N, 3.93. Found: C, 57.28; H, 5.17; N,3.97. ¹H-NMR(CDCl₃) δ: 0.82–0.91 (2H, m), 1.06 (3H, t, J=7.2 Hz),1.21–1.32 (2H, m), 1.51–1.70 (2H, m), 1.80–1.94 (2H, m), 3.04 (1H, bs),3.13–3.22 (1H, m), 3.90 (2H, t, J=6.4 Hz), 4.98 (2H, d, J=5.8 Hz), 7.65(1H, s), 8.25 (1H, s).

(5)4-Butoxy-3-chloromethyl-6,7-dichloro-2-cyclopropyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.87–0.95 (2H, m), 1.04 (3H, t, J=7.4 Hz), 1.22–1.37(2H, m), 1.50–1.69 (2H, m), 1.80-l.-95 (2H, m), 3.14–3.25 (1H, m), 3.93(2H, t, J=6.6 Hz), 5.03 (2H, s), 7.76 (1H, s), 8.45 (1H, s).

(6)2-(4-Butoxy-6,7-dichloro-2-cyclopropyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 197–198° C. Elemental analysis for C₂₅H₂₂N₂O₄Cl₂Calculated: C, 61.87; H, 4.57; N, 5.77.Found: C, 61.93; H, 4.50; N,5.84. ¹H-NMR(-CDCl₃) δ: 0.82–0.91 (2H, m), 1.00 (3H, t, J=7.3 Hz),1.26–1.37 (2H, m), 1.43–1.61 (2H, m), 1.75–1.90 (2H, m), 2.84–2.95 (1H,m), 3.98 (2H, t, J=6.8 Hz), 5.25 (2H, s), 7.69–7.84 (5H, m), 8.42 (1H,s).

(7)Tert-butyl(4-butoxy-6,7-dichloro-2-cyclopropyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 143–144° C. Elemental analysis for C₂₂H₂₈N₂O₄Cl₂Calculated: C, 58.03; H, 6.20; N, 6.15. Found: C, 58.09; H, 6.33; N,5.95. ¹H-NMR(CDCl₃) δ: 0.79–0.88 (2H, m), 1.04 (3H, t, J=7.3 Hz),1.25–1.39 (2H, m), 1.44 (9H, s), 1.48–1.67 (2H, m) 1.76–1.93 (2H, m),2.97–3.08 (1H, m), 3.86 (2H, t, J=6.6 Hz), 4.73 (2H, d, J=5.6 Hz), 4.95(1H, bs), 7.71 (1H, s), 838 (1H, s).

(8)3-(Aminomethyl)-4-butoxy-6,7-dichloro-2-cyclopropyl-1(2H)-isoquinolinehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 238° C. Elemental analysis for C₁7H211N20₂Cl₃ Calculated:C, 52.12; H, 5.40; N, 7.15. Found: C, 51.96; H, 5.30; N, 6.99.¹H-NMR(DMSO-d₆) δ: 0.84–0.92 (2H, m), 0.99 (3H, t, J7.3 Hz), 1.19–1.30(2H, m), 1.44–1.63 (2H, m), 1.77–1.91 (2H, m), 3.13–3.21 (1H, m), 3.93(2H, t, J=6.0 Hz), 4.38 (2H, bs), 7.85 (1H, s), 8.30 (1H, s), 8.78 (3H,bs).

Example 323-(Aminomethyl)-4-butoxy-6,7-dichloro-2-cyclopropylmethyl-1(2H)-isoquinolinehydrochloride

(1) Ethyl6,7-dichloro-2-cyclopropylmethyl-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to-that in Example 1 (1))

Melting point 109.5–110° C. Elemental analysis for C₁₆H₁₅NO₄Cl₂Calculated: C, 53.95; H, 4.24; N, 3.93. Found: C, 54.03; H, 4.04; N,3.95. ¹H-NMR(CDCl₃) δ: 0.32–0.54 (4H, m), 0.96–1.16 (1H, m), 1.48 (3H,t, J=7.2 Hz), 4.33 (2H, d, J=6.8 Hz), 4.52 (2H, q, J=7.2 Hz), 8.23 (1H,s), 8.51 (1H, s), 11.17 (1H, s).

(2) Ethyl4-butoxy-6,7-dichloro-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2)

¹H-NMR(CDCl₃) δ: 0.38–0.57 (4H, m):, 1.01 (3H1, t, J=7.4 Hz), 1.16–1.26(1H, m), 1.45 (3H, t, J=7.4 Hz), 1.47–1.62 (2H, m), 1.68–1.86 (2H, m),3.89–3.99 (4H, m), 4.47 (2H, q, J=7.4 Hz), 7.81 (1H, s), 8.51 (1H, s).

(3)4-Butoxy-6,7-dichloro-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 150–151° C. Elemental analysis for C₁₈H₁₉NO₄Cl₂Calculated: C, 56.26; H, 4.98; N, 3.65. Found: C, 56.45; H, 5.02; N,3.67. ¹H-NMR(CDCl₃) δ: 0.41–0.58 (4H, m), 1.00 (3H, t, J=7.3 Hz),1.20–1.33 (1H, m), 1.45–1.64 (2H, m), 1.76–1.90 (2H, m), 4.01 (2H, t,J=6.5 Hz), 4.06 (2H, d, J=7.4 Hz), 7.74 (1H, s), 8.46 (1H, s).

(4)4-Butoxy-6,7-dichloro-2-cyclopropylmethyl-3-hydroxymethyl-1(-2H)-isoquinoline(synthesized according to the method similar to that in Example 4 (4))

Melting point 130–130.5° C. Elemental analysis forC₁₈H₂₁NO₃Cl₂Calculated: C, 58.39; H, 5.72; N, 3.78. Found: C, 58.46; H,5.84; N, 3.77. ¹H-NMR(CDCl₃) δ: 0.46–0.58 (4H, m), 1.04(3H, t, J=7.4Hz), 1.08–1.24 (1H, m), 1.50–1.68 (2H, m), 1.79–1.94 (2H, m), 2.33 (1H,bs), 3.88 (2H, t, J=6.8 Hz), 4.19 (2H, d, J=7.0 Hz), 4.83 (2H, d, J=5.6Hz), 7.72 (1H, s), 8.42 (1H, s).

(5)4-Butoxy-3-chloromethyl-6,7-dichloro-2-cyclopropylmethyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4

¹H-NMR(CDCl₃) δ: 0.44–0.62 (4H, m), 1.02–1.15 (4H, m), 1.52–1.71 (2H,m), 1.83–1.97 (2H, m), 3.99 (2H, t, J=6.6 Hz), 4.20 (2H, d, J=6.6 Hz),4.83 (2H, s), 7.81 (1H, s), 8.51 (1H, s).

(6)2-(4-Butoxy-6,7-dichloro-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 162–163° C. Elemental analysis for C₂₆H₂₄N₂O₄Cl₂Calculated: C, 62.53; H, 4.84; N, 5.61. Found: C, 62.64; H, 4.77; N,5.61. ¹H-NMR(CDCl₃) δ: 0.47–0.50 (4H, m), 0.95–1–08 (4H, m), 1.43–1.62(2H, m), 1.78–1.92 (2H, m), 3.98 (2H, t, J=6.7 Hz), 4.15 (2H, d, J=6.6Hz), 5.05 (2H, s), 7.71–7.86 (5H, m), 8.49 (1H, s).

(7)Tert-butyl(4-butoxy-6,7-dichloro-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 1.41.5–142.5° C. Elemental analysis for C₂₃H₃₀N₂O₄Cl₂Calculated: C, 58.85; H, 6.44; N, 5.97. Found: C, 58.84; H, 6.32; N,6.04. ¹H-NMR(CDCl₃) δ: 0.50–0.59 (4H, m), 1.04 (3H, t, J=7.4 Hz),1.08–1.28 (1H, m), 1.47 (9H, s), 1.53–1.6.8 (2H, m), 1.80–1.94 (2H, m),3.86 (2H, t, J=6.4 Hz), 4.08 (2H, d, J=6.6 Hz), 4.52 (2H, d, J=5.8 Hz),4.87 (11H bs), 7.74 (1H, s), 8.45. (1H, s).

(8)3-(Aminomethyl)-4-butoxy-6,7-dichloro-2cyclopropylmethyl-1(2H)-isoquinolinehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 227–228° C. Elemental analysis for C₁₈H₂₃N₂O₂Cl₃Calculated: C, 53.28; H, 5.71; N, 6.90. Found: C, 53.18; H, 5.71; N,6.75. ¹H-NMR(DMSO-d₆) δ: 0.47 (4H, d, J=6.6 Hz), 1.00 (3H, t, J=7.3 Hz),1.13–1.26 (1H, m), 1.45–1.64 (2H, m), 1.78–1.92(4H, m), 3.96 (3H, t,J=6.4 Hz), 4.06 (6H, d,: J=6.6 Hz), 4.20 (2H, d, J=4.0 Hz), 7.92 (1H,s), 8.39 (1H, s), 8.72 (3H, bs).

Example 333-(Aminomethyl)-4-butoxy-6,7-dichloro-2-isopentyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6,7-dichloro-4-hydroxy-2-isopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 118–120° C. Elemental analysis for C₁₆H₁₅NO₄Cl₂Calculated: C, 54.85; H, 5.14; N, 3.76. Found: C, 54.63; H, 5.03; N,3.52. ¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.2 Hz), 1.47 (3H, t, J=7.2 Hz),1.58–1.65 (3H, m), 4.26–4.34 (2H, m), 4.52 (2H, q, J=7.2 Hz), 8.22 (1H,s), 8.51 (1H, s), 11.24 (1H, s).

(2) Ethyl4-butoxy-6,7-dichloro-2-isopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.2 Hz), 1.01 (3H, t, J=7.0 Hz),1.39–1.86 (10H, m), 3.91–3.98 (4H, m), 4.46 (2H, q, J=7.2 Hz), 7.80 (1H,s), 8.50 (1H, s).

(3)4-Butoxy-6,7-dichloro-2-isopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 100–101° C. Elemental analysis for C₁₉H₂₃NO₄Cl₂Calculated: C, 5.7.01; H, 5.79; N, 3.50. Found: C, 56.83; H, 5.88; N,3.51. ¹H-NMR(CDCl₃) δ: 0.94–1.03 (98H, m), 45–1.88 (7H, m), 3.99 (2H, t,J=6.4 Hz), 4.04–4.11 (2H, m), 5.59 (1H, bs), 7.76 (1H, s), 8.46 (1H, s).

(4-Butoxy-6,7-dichloro-3-hydroxymethyl-2-isopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 102–103.5° C. Elemental analysis for C₁H₂₅NO₃Cl₂Calculated: C, 59.07; H, 6.52; N, 3.63. Found: C, 58.78; H, 6.64; N,3.60. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.4 Hz),1.49–1.92 (7H, m), 2.56 (1H, bs), 3.86 (2H, t, J=6.5 Hz), 4.18–4.26(21H, m), 4.76 (2H, s), 7.69 (1H, s), (5)4-Butoxy-3-chloromethyl-6,7-dichloro-2-isopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.2 Hz), 1.05 (3H, t,

J=7.3 Hz), 1.52–1.96 (7H, m), 3.98 (2H, t, J=6.4 Hz), 4.10–4.25 (2H, m),4.75 (2H, s), 7.81 (1H, s), 8.50 (1H, s).

(6)2-[(4-Butoxy-6,7-dichloro-2-isopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 115–119° C. Elemental analysis for C₂₇H₂₆N₂O₄Cl₂Calculated: C, 62.92;H, 5.48; N, 5.43. Found: C, 63.10; H, 5.30; N,5.76. ¹H-NMR(CDCl₃) δ: 0.85 (6H, d, J=6.4 Hz), 1.00 (3H, t, J=7.2 Hz),1.38–1.63 (5H, m), 1.78–1.92 (2H, m), 3.99 (2H, t, J=6.8 Hz), 4.07–4.15(2H, m), 5.02 (2H, s), 7.73–7.90 (5H, m), 8.48 (1H, s).

(7)Tert-butyl(4-butoxy-6,7-dichloro-2-isopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 129–129° C. Elemental analysis for C₂₄H₃₄N₂O₄Cl₂Calculated: C, 59.38; H, 7.06; N, 5.77. Found: C, 59.48; H, 7.32; N,5.80. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.3 Hz),1.47 (9H, s), 1.52–1.699 (4H, m), 1.73–1.93 (3H, m), 3.83 (2H, t, J=6.5Hz), 4.06–4.14 (2H, m), 4.47 (2H, d, J=6.4 Hz), 4.72 (1H, bs), 7.75 (1H,s), 8.47 (1H, s).

(8)3-(Aminomethyl)-4-butoxy-6,7-dichloro-2-isopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 251–253° C. Elemental analysis for C₁₉H₂₇N₂O₂Cl₃Calculated: C, 54.10; H, 6.4.5; N, 6.64. Found: C, 54.13; H, 6.44; N,6.64. ¹H-NMR(DMSO-d₆) δ: 0.96 (6H, d, J=6.6 Hz), 1.00 (3H, t, J=7.3 Hz),1.42–1.92 (7H, m), 3.94 (2H, t, J=6.6 Hz), 4.05–4.13 (4H, m), 7.91 (1H,s), 8.38 (1H, s), 8.79 (3H, bs).

Example 343-(Aminomethyl)-6,7-dichloro-4-isobutoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6,7-dichloro-4-isobutoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.93 (9H, s), 1.08 (6H, d, J=6.6 Hz), 1.43 (3H, t,J=7.1 Hz), 2.04–2.19 (1H, m), 3.70 (2H, d, J=6.6 Hz), 4.04 (2H, bs),4.42 (2H, q, J=7.1 Hz), 7.83. (1H, s), 8.51 (1H, s).

(2)6,7-Dichloro-4-isobutoxy-2neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 156–157° C. Elemental analysis for C₁₉H₂₃NO₄Cl₂Calculated: C, 57.01; H, 5.79; N, 3.50. Found: C, 57.14; H, 5.55; N,3.58. ¹H-NMR(CDCl₃) δ: 0.93 (9H, s), 1.10 (6H, d, J=6.6 Hz), 2.11–2.24(1H, m), 3.78 (22H, d, J=6.2 Hz), 4.21 (2H, bs), 7.76(1H, s), 8.43 (1H,s). (3)6,7-Dichloro-3-hydroxyethyl-4-isobutoxy-2neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 180–180.5° C. Elemental analysis for C₁₉H₂₅NO₃Cl₂ ½H₂OCalculated: C, 58.39; H, 6.58; N, 3.58 Found: C, 58.52; H, 6.68; N,3.57. ¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.16 (6H, d, J=6.6 Hz), 2.12–2.29(1H, m), 3.09 (1H, bs), 3.67 (2H, d, J=6.2 Hz), 4.21 (2H, bs), 4.83 (2H,bs), 7.67–7.68 (1H, m), 8.22–8.26 (1H, m).

(4)3-Chloromethyl-6,7-dichloro-4-isobutoxy-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.15 (6H, d, J=6.6 Hz), 2.15–2.25 (1H,m), 3.71 (2H, d, J=6.2 Hz), 4.19 (2H, bs), 4.85 (2H, bs), 7.81 (1H, s),8.50 (1H, s).

(5)2-(6,7-Dichloro-1-oxo-4-isobutoxy-2-neopentyl-1,2-dihydro-3-isoquinolinyl)methyl-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 147–148° C. Elemental analysis for C₂₇H₂₈N₂O₄Cl₂Calculated: C, 62.92; H, 5.48; N, 5.43.Found: C, 62.85; H, 5.59; N,5.42. ¹H-NMR(CDCl₃) δ: 100 (9H, s), 1.11 (6H, d, J=6.6 Hz), 2.17–2.31(1H, m), 3.76 (2H, d, J=6.6 Hz), 4.03 (2H, bs), 5.05 (2H, s), 7.71–7.84(5H, m), 8.47 (1H, s).

(6)Tert-butyl(6,7-dichloro-4-isobutoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 171–172° C. Elemental analysis for C₂₄H₃₄N₂O₄Cl₂Calculated: C, 59.38; H, 7.06; N, 5.77. Found: C, 59.49; H, 6.96; N,5.91. ¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.13 (6H, d, J=6.6 Hz), 1.46 (9H,s), 2.13–2.27 (11, m), 3.61 (2H, d, J=6.2 Hz), 4.12 (2H, bs), 4.54 (2H,d, J=5.4 Hz), 4.77(1H, bs), 7.76 (1H, s), 8.45 (1H, s).

(7)3-(Aminomethyl)-6,7-dichloro-4-isobutoxy-2neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 254–256° C. Elemental analysis for C₁₉H₂₇N₂O₂Cl₃Calculated: C, 54.10; H, 6.45; N, 6.64. Found: C, 53.76; H, 6.40; N,6.47. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 1.10 (6H, d, J=6.6 Hz), 2.14–2.27(1H, m), 3.73 (2H, d, J=6.6 Hz), 4.11 (2H, bs), 4.24 (2H, s), 7.89 (1H,s), 8.38 (1H, s), 8.63 (3H, bs).

Example 353-(Aminomethyl)-4-butoxy-6,7-dichloro-2-[3oxo-(1pyrrolidinyl)propyl]-1(2H)-isoquinolinonehydrochloride

(1) tert-butyl6,7-dichloro-2-(3-ethoxy-3-oxypropyl)-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1(1))

Melting point 114–115° C. Elemental analysis for C₁₉H₂₁NO₆Cl₂Calculated: C, 53.04; H, 4.92; N, 3.26. Found: C, 53.04; H, 4.94; N,3.16. ¹H-NMR(CDCl₃) δ: 1.24 (3H, t, J=7.2 Hz), 1.66 (9H, s), 2.86–2.93(2H, m), 4.15 (2H, q, J=7.2 Hz), 4.39–4.47 (2H, m), 8.22 (1H, s), 8.49(1H, s), 11.30 (1H, s).

(2) Tert-butyl4-butoxy-6,7-dichloro-2-(3-ethoxy-3-oxypropyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

Melting point 89–90° C. Elemental analysis for C₂₃H₂₉NO₆Cl₂ Calculated:C, 56.80; H, 6.01; N, 2.88. Found: C, 56.84; H, 5.93; N, 2.92.¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.4 Hz), 1.26 (3H, t, J=7.1 Hz),1.48–1.61 (2H, m), 1.64 (9H, s), 1.74–1.85 (2H, m), 2.82–2.90 (2H, m),3.95 (2H, t, J=6.4 Hz), 4.12–4.22(4H, m), 7.80(1H, s), 8.48 (1H, s).

(3) A solution of tert-butyl4-butoxy-6,7-dichloro-2-(3ethoxy-3-oxypropyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(2.43 g, 5 mmol) in trifluoroacetic acid (10 ml) was stirred at roomtemperature for 2 h. The reaction mixture was concentrated under reducedpressure and the residue was recrystallized from ethyl acetate-diisopropyl ether to give4-butoxy-6,7-dichloro-2-(3-ethoxy-3-oxypropyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (2.06 g, 95.8%) as crystals.

Melting point 117.5–118° C. Elemental analysis for C₁₉H₂₁NO₆Cl₂Calculated: 53.304; H, 4.92; N, 3.26. Found: C, 53.20; H, 4.83; N, 3.30.¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.3 Hz), 1.24 (3H, t, J=7.2 Hz),1.44–1.63 (2H, m), 1.75–1.89 (2H, m), 2.96 (2H, t, J=7.3.Hz), 4.00 (2H,t, J=6.4 Hz), 4.15 (2H, t, J=7.2 Hz), 4.30 (2H, t, J=7.2 Hz), 5.01 (1H,bs), 7.83 (1H, s), 8.50 (1H, s).

(4) Ethyl3-[4-butoxy-6,7-dichloro-3-hydroxymethyl-1oxo-2(1H)-isoquinolinyl]propionate(synthesized according to the method similar to that in Example 4 (4))

Melting point 122–123° C. Elemental analysis for C₁₉H₂₃NO₅Cl₂Calculated: C, 544.82; H, 5.57; N, 3.36. Found: C, 54.71; H, 5.51; N,3.37. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.4 Hz), 1.23 (3H, t, J=7.2 Hz),1.49–1.67 (2H, m), 1.78–1.92 (2H, m), 2.82. (1H, bs), 2.92 (2H, t, J=6.9Hz), 3.89 (2H, t, J=6.4 Hz), 4.13 (2H, q, J=7.2 Hz), 4.43 (2H, t, J=6.9Hz), 4.86 (2H, s), 7.78 (1H, s), 8.44 (1H, s).

(5) Ethyl3-[4-butoxy-3-chloromethyl-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl]propionate(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.05 (3H, t, J=7.1 Hz), 1.22 (3H, t, J=7.0 Hz),1.51–1.66 (2H, m), 1.70–1.95 (2H, m), 2.89 (2H, t, J=6.8 Hz), 3.96 (2H,t, J=6.6 Hz), 4.11 (2H, q, J=7.0 Hz), 4.42 (2H, t, J=6.8 Hz), 4.95 (2H,s), 7.81 (1H, s), 8.49 (1H, s).

(6) Ethyl3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)-isoquinolinyl]propionate

Melting point 167–169° C. Elemental analysis for C₂₇H₂₆N₂O₆Cl₂Calculated: C, 59.46; H, 4.80; N, 5.14. Found: C, 59.54; H, 4.66; N,5.11. ¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.1 Hz), 1.19 (3H, t, J=7.1 Hz),1.47–1.61 (2H, m), 1.78–1.93 (2H, m), 2.77 (2H, t, J=7.0 Hz), 3.97 (2H,t, J=6.7 Hz), 4.07 (2H, q, J=7.1 Hz), 4.39 (2H, t, J=7.0 Hz), 5.13 (2H,s), 7.72–7.87(5H, m), 8.47 (1H, s).

(7) A mixture of ethyl3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)isoquinolinyl]propionate (1.36 g, 2.5 mmol) in 6N hydrochloric acid(15 ml) and acetic acid (15 ml) was refluxed with stirring for 2 h. Thereaction mixture was concentrated under reduced pressure, and theresidue was recrystallized from tetrahydrofuran-diisopropyl ether togive3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)-isoquinolinyl]propionicacid (1.08 g, 83.7%) as crystals.

Melting point 196–197° C. Elemental analysis for C₂₆H₂₂N₂C₆Cl₂ 2H₂OCalculated: C, 54.26; H, 4.74; N, 5.06. Found: C, 54.32; H, 4.38; N,5.13. ¹H-NMR(CDCl₃) δ: 0.99 (3H, t, J=7.1 Hz), 1.42–1.60 (2H, m),1.77–1.91 (2H, m), 2.76 (2H, t, J=7.1 Hz), 3.94 (2H, t, J=6.8 Hz), 4.41(2H, t, J=7.1 Hz), 5.13 (2H, s), 7.73–7.86 (5H, m), 8.44 (1H, s).

(8) A solution of3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)isoquinolinyl]propionicacid (1.03 g, 2.4 mmol), pyrrolidine (0.20 ml, 2.4 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g, 2.4mmol) and 1-hydroxybenzotriazole (0.37 g, 2.4 mmol) inN,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas recrystallized from tetrahydrofuran-diisopropyl ether to give2-[[4-butoxy-6,7-dichloro-1-oxo-2-[3-oxo-3-(1-pyrrolidinyl)propyl]-1,2-dihydro-3-isoquinolinyl]-methyl]-1H-isoindole-1,3(2H)-dione(0.72 g, 66.1%) as crystals.

Melting point 222–222.5° C. Elemental analysis for C₂₉H₂₉N₃O₅Cl₂Calculated: C, 61.01; H, 5.12; N, 7.37. Found: C, 60.91; H, 5.16; N,7.21. ¹H-NMR(CDCl₃) δ: 0.98 (3H, t, J=7.1 Hz), 1.41–1.59 (2H, m),1.74–1.92 (6H, m), 2.78 (2H, t, J=7.0 Hz), 3.25–3.38(4H, m), 3.94 (2H,t, J=6.8 Hz), 4.46 (2H, t, J=7.0 Hz), 5.23 (2H, s), 7.70–7.85 (5H, m),8.47 (1H, s).

(9),Tert-butyl{4-butoxy-6,7-dichloro-1-oxo-{3-oxo-3-(1pyrrolidinyl)propyl}-1,2-dihydro-3-isoquinolinyl}-methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 215–217° C. Elemental analysis for C₂₆H₃₅N₃O₅Cl₂Calculated: C, 57.78; H, 6.53; N, 7.77. Found: C, 57.95; H, 6.43; N,7.60. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.3 Hz), 1.44 (9H, s), 1.51–1.62(2H, m), 1.79–1.95 (6H, m), 2.86 (2H, t, J=6.8 Hz), 3.36–3.45 (4H, m),3.88 (2H, t, J=6.6 Hz), 4.73 (2H, t, J=6.8 Hz), 4.60 (2H, d, J=5.4 Hz),5.80 (1H, bs), 7.79 (1H, s), 8.45 (1H, s).

(10)3-(Aminomethyl)-4-butoxy-6,7-dichloro-2-{3-oxo-(1-pyrrolidinyl)propyl}-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 206–206.5° C. Elemental analysis for C₂₁H₂₈N₃O₃Cl₃ 3/2H₂OCalculated: C, 50.06; H, 6.20; N, 8.34. Found: C, 49.72; H, 6.02; N,8.23. ¹H-NMR(DMSO-₆) δ: 0.99 (3H, d, J=7.4 Hz), 1.45–1.63 (2H, m),1.71–1.883.(6H, m), 2.76 (2H, t, J=6.6 Hz), 3.23–3.38 (4H, m), 3.93 (2H,t, J=6.4 Hz), 4.21–4.28 (4H, m), 7.91 (1H, s), 8.36 (1H, s), 8.79 (3H,bs).

Example 363-(Aminomethyl)-4-butoxy-6,7-dichloro-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl4-butoxy-6,7-dichloro-4-hydroxy-2-methyl-1oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 78–80° C. Elemental analysis for C₁₇H₁₉NO₆Cl₂¼H₂OCalculated: C, 54.20; H, 5.22; N, 3.72 Found: C, 54.16; H, 5.06; N,3.61. ¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.1 Hz), 1.44 (3H, t, J=7.2 Hz),1.47–1.58 (2H, m), 1.72–1.86 (2H, m), 3.51 (3H, s), 3.95 (2H, t, J=6.5Hz), 4.47 (2H, q, J=7.2 Hz), 7.82 (1H, s), 8.51 (1H, s).

(2)4-Butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 209–210° C. Elemental analysis for C₁₅H₁₅NO₄Cl₂Calculated: C, 52.34; H, 4.39; N, 4.07. Found: C, 52.21; H, 4.27; N,3.78. ¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.3 Hz), 1.49–1.60 (2H, m),1.74–1.84 (2H, m), 3.58 (3H, s), 3.99 (2H, t, J=6.6 Hz), 5.03 (1H, bs),7.83 (1H, s), 8.49 (1H, s).

(3) 4-Butoxy-6,7-dichloro-3-hydroxymethyl-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 146–147° C. Elemental analysis for C₁₅H₁₇NO₃Cl₂Calculated: C, 54.56; H, 5.19; N, 4.24. Found: C, 54.32; H, 4.98; N,4.14. ¹H-NMR(CDCl₃) δ: 1.04 (3H, t, J=7.3 Hz), 1.44–1.67 (2H, m),1.77–1.91 (2H, m), 2.52 (1H, bs), 3.71 (3H, s), 3.83 (2H, t, J=6.6 Hz),4.79 (2H, s), 7.66 (1H, s), 8.38 (1H, s).

(4) 4-Butoxy-3-chloromethyl-6,7-dichloro-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.05 (3H, t, J=7.1 Hz), 1.52–1.76 (2H, m), 1.82–1.96(2H, m), 3.72 (3H, s), 3.97 (22H, t, J=6.5 Hz), 4.77 (2H, s), 7.81 (1H,s), 8.51 (1H, s).

(5)2-[(4-Butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 228–228.5° C. Elemental analysis for C₂₃H₂₀N₂O₄Cl₂Calculated: C, 60.14; H, 4.39; N, 6.10. Found: C, 59.92; H, 4.35; N,6.13. ¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.2 Hz), 1.46–1.64 (2H, m),1.80–1.94 (2H, m), 3.56 (3H, s), 4.03 (2H, t, J=6.8 Hz), 5.06 (2H, s),7.73–7.88 (5H, m), 8.48 (1H, s).

(6)Tert-butyl(4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 159.5–160° C. Elemental analysis for C₂₀H₂₆N₂O₄Cl₂Calculated: C, 55.95; H, 6.10; N, 6.52. Found: C, 55.93; H, 6.18; N,6.29. ¹H-NMR(CDCl₃) δ: 1.04 (3H, t, J=7.1 Hz), 1.47 (9H, s), 1.49–1.63(2H, m), 1.73–1.93 (2H, m), 3.62 (3H, s), 3.83 (2H, t, J=6.6 Hz), 4.52(2H, d, J=5.4 Hz), 4.82 (1H, bs), 7.75 (1H, s), 8.46 (1H, s).(7)3-(Aminomethyl)_4-butoxy-6,7-dichloro-2-mehtyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 251–252° C. Calculated: C, 48.67; H, 5.31; N, 7.57. Found:C, 48.69; H, 5.37; N, 7.79. ¹H-NMR(DMSO-d₆) δ: 0.99 (3H, t, J=7.3 Hz),1.45–1.63 (2H, m), 1.77–1.91 (2H, m), 3.61 (3H, s), 3.92 (2H, t, J=6.4Hz), 4.23 (2H, s), 7.91 (1H, s), 8.36 (1H, s), 8.79 (3H, bs).

Example 373-(1-Aminoethyl)-4-butoxy-6,7-dichloro-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) To a solution of dimethyl sulfoxide;(1.7 ml, 24 mmol) intetrahydrofuran (10 mmol) was added oxalyl chloride (1.05 ml, 12 mmol)at −78° C. and the obtained mixture was stirred at −78° C. for 15 min.To the mixture was added4-butoxy-6,7-dichloro-3-hydroxymethyl-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 36 (3))(2.43 g, 5mmol) and the obtained mixture was stirred at −78° C. for 5min. To the mixture was added triethylamine (5.6 ml, 40mmol) and theobtained mixture was stirred at room temperature for 30 min. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasrecrystallized from tetrahydrofuran-diisopropyl ether to give4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinealdehyde(2.14 g, 81.7%) as crystals.

Melting point 114–115° C. Elemental analysis for C₁₅H₁₅NO₃Cl₂Calculated: C, 54.90; H, 4.61; N, 4.27. Found: C, 54.71; H, 4.39; N,4.21. ¹H-NMR(CDCl₃) δ: 1.04 (3H, t, J=7.3 Hz), 1.49–1.68 (2H, m),1.84–1.98 (2H, m), 3.82 (3H, s), 4.05 (2H, t, J=6.6 Hz), 7.96 (2H, s),8.56 (1H, s), 10.24 (1H, s).

(2) To a solution of4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinealdehyde(0.98 g, 24 mmol) in tetrahydrofuran (20 mmol) was added 3Nmethylmagnesium bromide tetrahydrofuran solution (1.5 ml, 4.5 mmol) at0° C. and the obtained mixture was stirred at 0° C. for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-n-hexane to give4-butoxy-6,7-dichloro-3-(1-hydroxyethyl)-2-methyl-1(2H)-isoquinolinone(0.95 g, 92.2%) as crystals.

Melting point 123–123.5° C. Elemental analysis for C₁₆H₁₉NO₃Cl₂Calculated: C, 55.83; H, 5.56; N, 4.07. Found: C, 55.81; H, 5.59; N,3.86. ¹H-NMR(CDCl₃) δ: 1.04 (3H, t, J=7.3 Hz), 1.49–1.63 (2H, m), 1.64(3H, d, J=7.0 Hz), 1.78–1.92 (2H, m), 3.26 (1H, bs), 3.70–3.84 (5H, m),5.63 (1H, q, J=7.0 Hz), 7.59 (1H, s), 8.36 (1H, s).

(3)4-Butoxy-3-(1-chloroethyl)-6,7-dichloro-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.05 (3H, t, J=7.3 Hz), 1.51–1.69 (2H, m), 1.82–1.92(2H, m), 1.96 (3H, d, J=7.2 Hz), 3.83 (3H, s), 3.88–3.96 (2H, m),5.92–6.00 (1H, m), 7.81 (1H, s), 8.50 (1H, s).

(4)2-[1-(4-Butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)ethyl]-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Elemental analysis for C₂₄H₂₂N₂O₄Cl₂ Calculated: C, 60.90; H, 4.68; N,5.92. Found: C, 60.76; H, 4.38; N, 5.72. ¹H-NMR(CDCl₃) δ: 0.99 (3H, t,J=7.3 Hz), 1.41–1.52 (2H, m), 1.77–1.87 (2H, m), 2.08 (3H, d, J=7.6 Hz),3.67 (3H, s), 3.84–3.95 (1H, m), 4.405–4.16 (1H, m), 5.81 (1H, q, J=7.6Hz), 7.72–7.87 (5H, m), 8.47 (1H, s).

(5) Tert-butyl1-(4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)ethylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 118–118.5° C. Elemental analysis for C₂₁H₂₈N₂O₄Cl₂Calculated: C, 5:6.89; H, 6.3.7; N, 6.32. Found: C, 57.11; H, 6.58; N,6.13. ¹H-NMR(CDCl₃) δ: 1.04 (3H, t, J=7.4 Hz), 1.43 (9H, s), 1.54 (3H,d, J=7.0 Hz), 1.56–1.74 (2H, m), 1.84–1.98 (2H, m), 3.73 (3H, s),3.82–4.03 (2H, m), 5.20–5.29 (1H, m), 5.57 (1H, bs), 7.72 (1H, s), 8.48(1H, s).

(6) 3-(1-Aminobutyl)-4-butoxy-6,7-dichloro-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 224–225° C. Elemental analysis for C₁₆H₂₁N₂O₂Cl₃Calculated: C, 50.61; H, 5.57; N, 7.38. Found: C, 50.38; H, 5.63; N,7.28. ¹H-NMR(DMSO-d₆) δ: 0.99 (3H, t J=7.3 Hz), 1.44–1.62 (2H, m), 1.69(3H, d, J=7.4 Hz), 1.81–1.92 (2H, m), 3.61 (3H, s), 3.92 (2H, t, J=6.8Hz), 4.95 (2H, bs), 7.87 (1H, s), 8.36 (1H, s), 8.87 (3H, bs).

Example 383-(1-Aminobutyl)-4-butoxy-6,7-dichloro-2-methyl-1(2H)-isoquinolinonehydrochloride

(1)4-Butoxy-6,7-dichloro-3-(1-hydroxybutyl)-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 37 (2))

Melting point 105.5–106° C. Elemental analysis for C₁₈H₂₃NO₃Cl₂Calculated: C, 58.07; H, 6.23; N, 3.76. Found: C, 58.09; H, 6.53; N,3.57. ¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.3 Hz), 1.04 (3H, t, J=7.3 Hz),1.31–2.10 (8H, m), 2.98 (1H, bs), 3.75 (3H, s), 3.82 (2H, t, J=6.4 Hz),5.31–5.40 (1H, m), 7.66 (1H, s), 8.41 (1H, s).

(2)4-Butoxy-3-(1-chlorobutyl)-6,7-dichloro-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.97 (3H, t, J=7.4 Hz), 1.05 (3H, t, J=7.3 Hz),1.22–1.76 (4H, m), 1.80–1.95 (2H, m), 2.17–2.35 (2H, m), 3.79 (3H, s),3.91 (2H, t, J=6.2 Hz), 5.79 (1H, bs), 7.81 (1H, s), 8.50 (1H, s).

(3)2-[1-(4-Butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)butyl]-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Elemental analysis for C₂₆H₂₆N₂O₄Cl₂ Calculated: C, 62.28; H, 5.23; N,5.59. Found: C, 62.05; H, 5.02; N, 5.60. ¹H-NMR(CDCl₃) δ: 1.00 (3H, t,J=7.2 Hz), 1.03 (3H, t, J=7.2 Hz), 1.37–1.62 (4H, m), 1.78–1.91 (2H, m),1.99–2.17 (1H, m), 2.89–3.08 (1H, m), 3.65 (3H, s), 3.75–3.93 (1H, m),4.08–4.19 (1H, m), 5.64–5.72 (1H, m), 7.70–7.90 (5H, m), 8.47 (1H, s).

(4) Tert-butyl1-(4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)butylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Elemental analysis for C₂₃H₃₂N₂O₄Cl₂ Calculated: C, 58.60; H, 6.84; N,5.94. Found: C, 58.67; H, 6.62; N, 5.82. ¹H-NMR(CDCl₃) δ: 0.87 (3H, t,J=7.1 Hz), 1.07 (3H, t, J=7.4 Hz), 1.43 (9H, s), 1.44–1.98 (8H, m), 3.74(3H, s), 3.82–3.97 (2H, m), 5.12 (1H, bs), 5.37 (1H, bs), 7.71 (1H, s),8.48 (1H, s).

(5) 3-(1-Aminobutyl)-4-butoxy-6,7-dichloro-2-methyl-1(2H)-isoquinolinehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 217–218° C. Elemental analysis for C₁₈H₂₅N₂O₂Cl₃ ½H₂OCalculated: C, 51.87; H, 6.29; N, 6.72. Found: C, 51.66; H, 6.44; N,6.62. ¹H-NMR(DMSO-d₆) δ: 0.92 (3H, t, J=7.4 Hz), 0.99 (3H, t, J=7.4 Hz),1.26–1.59 (4H, m), 1.83–2.21 (4H, m), 3.59 (3H, s), 3.82–3.93 (2H, m),4.88 (1H, bs), 7.88 (1H, s), 8.36 (1H, s), 9.06 (3H, bs).

Example 393-(1-Amino-3-methylbutyl)-4-butoxy-6,7-dichloro-2-methyl-1(2H)-isoquinolinonehydrochloride

(1)4-Butoxy-6,7-dichloro-3-(1-hydroxy-3-methylbutyl)-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 37 (2))

Melting point 121–122° C. Elemental analysis for C₁₉H₂₅NO₃Cl₂Calculated: C, 59.07; H, 6.52; N, 3.63. Found: C, 59.13; H, 6.54; N,3.51. ¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.4 Hz),1.50–1.67 (3H, m), 1.79–2.04 (4H m), 2.90 (1H, bs), 3.74 (3H, s),3.77–3.89 (2H, m), 5.39–5.46 (1H, m), 7.66 (1H, s), 8.41 (1H, s).

(2)4-Butoxy-3-(1-chloro-3-methylbutyl)-6,7-dichloro-2-methyl-1(2H)-isoquinoline(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.95 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz), 1.05(3H, t, J=7.3 Hz), 1.52–1.99 (5H, m), 2.13–2.26 (2H, m), 3.79 (3H, s),3.93 (2H, t, J=6.6 Hz), 5.90 (1H, bs), 7.81 (1H, s), 8.50 (1H, s).

(3)2-[1-(4-Butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isquinolinyl)-3-methylbutyl]-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Elemental analysis for C₂₇H₂₈N₂O₄Cl₂ Calculated: C, 62.69; H, 5.48; N,5.43. Found: C, 62.92; H, 5.29; N, 5.39. ¹H-NMR(CDCl₃) δ: 0.81–1.07 (9H,m), 1.40–1.54 (2H, m), 1.63–1.92 (4H, m), 3.03–3.15 (1H, m), 3.72 (3H,s), 3.79–3.90 (1H, m), 4.07–4.19 (1H, m), 5.74–5.82 (1H, m), 7.72–7.85(5H, m), 8.47 (1H, s).

(4) Tert-butyl1-(4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-3methylbutylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Elemental analysis for C₂₄H₃₄N₂O₄Cl₂ Calculated: C, 59.38; H, 7.06; N,5.77. Found: C, 59.31; H, 6.96; N, 5.53. ¹H-NMR(CDCl₃) δ: 0.99 (3H, d,J=6.6 Hz), 1.01 (3H, d, J=6.6 Hz), 1.06 (3H, t, J=7.4 Hz), 1.43 (9H, s),1.46–1.69 (4H, m), 1.74–1.95 (3H, m), 3.73 (3H, s), 3.83–3.98 (2H, m),5.21 (1H, bs), 5.31 (1H, bs), 7.71 (1H, s), 8.48 (1H, s).

(5)3-(1-Amino-3-methylbutyl)-4-butoxy-6,7-dichloro-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 212.5–213.5° C. Elemental analysis for C₁₉H₂₇N₂O₂Cl₃Calculated: C, 54.10; H, 6.45; N, 6.64. Found: C, 53.92; H, 6.55; N,6.47. ¹H-NMR(DMSO-d₆) δ: 0.93–0.97 (6H, m), 0.99 (3H, t, J=7.4 Hz),1.42–2.18 (7H, m), 3.59 (3H, s), 3.89 (2H, bs), 5.05 (1H, bs), 7.89 (1H,s), 8.36 (1H, s), 9.18 (3H, bs).

Example 403-(1-Aminohexyl)-4-butoxy-6,7-dichloro-2-methyl-1(2H)-isoquinolinonehydrochloride

(1) 4-Butoxy-6,7-dichloro-3-(1-hydroxyhexyl)-2-methyl-1(2H)-isoquinoline(synthesized according to the method similar to that in Example 37 (2))

Melting point 95–96° C. Elemental analysis for C₂₀H₂₇NO₃Cl₂ Calculated:C, 60.00; H, 6.80; N, 3.50. Found: C, 59.90; H, 6.75; N, 3.45.¹H-NMR(CDCl₃) δ: 0.87–0.93(3H, m), 1.04 (3H, t, J=7.2 Hz), 1.33–1.35(4H, m), 1.49–2.05 (8H, m), 2.99 (1H, bs), 3.74 (3H, s), 3.81 (2H, t,J=6.4 Hz), 5.28–5.38 (1H, m), 7.64 (1H, s), 8.40 (1H, s).

(2)4-Butoxy-3-(1-chlorohexyl)-6,7-dichloro-2-methyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.82–0.91 (3H, m), 1.05 (3H, t, J=7.3 Hz), 1.22–1.39(6H, m), 1.51–1.76 (4H, m), 1.80–1.95 (2H, m), 3.79 (3H, s), 3.91 (2H,t, J=6.2 Hz), 5.78 (1H, bs), 7.81 (1H, s), 8.50 (1H, s).

(3)2-[1-(4-Butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)hexyl]-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Elemental analysis for C₂₈H₃₀N₂O₄Cl₂ Calculated: C, 63.52; H, 5.71; N,5.29. Found: C, 63.25; H, 5.78; N, 5.03. ¹H-NMR(CDCl₃) δ: 0.90 (3H, t,J=7.0 Hz), 1.00 (3H, t, J=7.3 Hz), 1.30–1.59 (8H, m), 1.77–1.91 (2H, m),2.01–2.14 (1H, m), 2.97–3.04 (1H, m), 3.70 (3H, s), 3.80–3.92 (1H, m),4.07–4.18 (1H, m), 5.61–5.69 (1H, m), 7.72–7.85 (5H, m), 8.47 (1H, s).

(4) Tert-butyl1-(4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)hexylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Elemental analysis for C₂₅H₃₆N₂O₄Cl₂ Calculated: C, 60.12; H, 7.26; N,5.61. Found: C, 59.95; H, 7.04; N, 5.53. ¹H-NMR(CDCl₃) δ: 0.88 (3H, t,J=6.0 Hz), 1.06 (3H, t, J=7.4 Hz), 1.22–1.32 (4H, m), 1.43 (9H, s),1.50–1.69 (4H, m), 1.74–1.98 (4H, m), 3.73 (3H, s), 3.82–3.96 (2H, m),5.10–5.12 (1H, m), 5.37 (1H, bs), 7.71 (1H, s), 8.48 (1H, s).

(5) 3-(1-Aminohexyl)-4-butoxy-6,7-dichloro-2-methyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 199.5–200° C. Elemental analysis for C₂₀H₂₉N₂O₂Cl₃ ½H₂OCalculated: C, 54.00; H, 6.80; N, 6.30. Found: C, 54.18; H, 6.87; N,6.14. ¹H-NMR(DMSO-d₆) δ: 0.85–0.88 (3H, m), 0.99 (3H, t, J=7.3. Hz),1.26–1.62 (7H, m), 1.83–2.18 (4H, m), 3.59 (3H, s), 3.81–3.92 (2H, m),4.87 (1H, bs), 7.89 (1H, s), 8.36 (1H, s), 9.09 (3H, bs).

Example 413-[(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl]-N-isopropylpropanamidehydrochloride

(1)3-[4-Butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-1,2-dihydro-3-isoquinolinyl]-N-isopropylpropanamide(synthesized according to the method similar to that in Example 35 (8))

Melting point 232–232.5° C. Elemental analysis for C₂₈H₂₉N₃O₅Cl₂Calculated: C, 60.22; H, 5.23; N, 7.52. Found: C, 59.98; H, 5.48; N,7.41. ¹H-NMR(CDCl₃) δ: 0.99 (3H, t, J=7.3 Hz), 1.05 (6H, d, J=6.6 Hz),1.44–1.59 (2H, m), 1.74–1.91 (2H, m), 2.6.6 (2H, t, J=6.8 Hz), 3.92 (2H,t, J=6.8 Hz), 3.92–4.02 (1H, m), 4.47 (2H, t, J=7.0 Hz), 5.15 (2H, s),5.76 (2H, d, J=7.6 Hz), 7.70–7.86 (5H, m), 8.43 (1H, s).

(2)Tert-butyl{4-butoxy-6,7-dichloro-2-{3-(isopropylamino)-3-oxypropyl}-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 221–221.5° C. Elemental analysis for C₂₅H₃₅N₃O₅Cl₂Calculated: C, 56.82; H, 6.68; N, 7.95. Found: C, 56.72; H, 6.51; N,7.93. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.1 Hz), 1.06 (6H, d, J=6.6 Hz),1.46 (9H, s), 1.51–1.66 (2H, m), 1.74–1.94 (2H, m), 2.71 (2H, t, J=7.0Hz), 3.87 (3H, t, J=6.6 Hz), 3.94–4.08 (1H, m), 4.35 (2H, t, J=7.0 Hz),4.56 (2H, d, J=5.8 Hz), 5.69 (1 H, bs), 6.01 (1H, bs), 7.79 (1H, s),8.43 (1H, s).

(3)3-[(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl]-N-isopropylpropanamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 189–191° C. Elemental analysis for C₂₀H₂₈N₃O₃Cl₃ 2H₂OCalculated: C, 47.96; H, 6.44; N, 8.39. Found: C, 48.07; H, 6.05; N,8.36. ¹H-NMR(DMSO-d₆) δ: 0.95 (6H, d, J=6.6 Hz) 0.99 (3H, t, J=7.3 Hz),1.44–1.63 (2H, m), 1.77–1.91 (2H, m), 2.56 (2H, t, J=6.6 Hz), 3.71–3.82(1H, m), 3.91 (2H, t, J=6.6 Hz), 4.20–4.31 (4H, m), 4.84 (2H, s), 7.92(1H, s), 8.02 (1H, d, J=7.4 Hz), 8.38 (1H, s), 8.75 (3H, bs).

Example 423-{3-(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl}-N-phenylpropanamidehydrochloride

(1)3-[4-Butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-1,2-dihydro-3-isoquinolinyl]-N-phenylpropanamide(synthesized according to the method similar to that in Example 35 (8))

Melting point 204–206° C. Elemental analysis for C₃₁H₂₇N₃O₅Cl₂Calculated: C, 62.84; H, 4.59; N, 7.09. Found: C, 62.46; H, 4.66; N,7.08. ¹H-NMR(CDCl₃) δ: 0.97 (3H, t, J=7.3 Hz), 1.38–1.57 (2H, m),1.78–1.89 (2H, m), 2.88 (2H, t, J=6.8 Hz), 3.87 (2H, t, J=6.8 Hz), 4.57(2H, t, J=6.6 Hz), 5.16 (2H, s), 7.03–7.10 (1H, m), 7.23–7.31 (2H, m),7.46–7.51 (2H, m), 7.69–7.85 (5H, m), 8.34 (1H, s), 8.52 (1H, s).

(2)Tert-butyl{2-(2-anilino-3-oxopropyl)-4-butoxy-6,7-dichloro-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 219–220° C. Elemental analysis for C₂₈H₃₃N₃O₅Cl₂Calculated: C, 59.79; H, 5.91; N, 7.47. Found: C, 59.92; H, 5.84; N,7.42. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.3 Hz), 1.46 (9H, s), 1.47–1.65(2H, m), 1.78–1.93 (2H, m), 2.90 (2H, t, J=7.2 Hz), 3.83 (2H, t, J=6.6Hz), 4.48 (2H, t, J=7.2 Hz), 4.60 (2H, d, J=5.8 Hz), 5.34 (1H, bs),7.04–7.11 (1H, m), 7.25–7.33 (2H, m), 7.55–7.59 (2H, m), 7.76 (1H, s),8.41 (1H, s), 8.72 (1H, bs).

(3)3-{3-(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl}-N-phenylpropanamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 243–244° C. Elemental analysis, for C₂₃H₂₆N₃O₃Cl₃Calculated: C, 55.38; H, 5.25; N, 8.42. Found: C, 55.31; H, 5.45; N,8.27. ¹H-NMR(DMSO-d₆) δ: 0.97 (3H, t, J=7.3 Hz), 1.40–1.60 (2H, m),1.73–1.87 (2H, m), 2.83 (2H, t, J=6.4 Hz), 3.84 (2H, t, J=6.4 Hz),4.31–4.34 (4H, m), 6.99–7.06 (1H, m), 7.23–7.31 (2H, m), 7.54–7.58 (2H,m), 7.91 (1H, s), 8.40 (1H, s), 8.65 (3H, bs), 10.23 (1H, s),

Example 433-(Aminomethyl)-4-butoxy-6,7-dichloro-2-{3-oxo-3-(1,3-thiazolidin-3-yl)propyl}-1(2H)-isoquinolinonehydrochloride

(1)2-[4-Butoxy-6,7-dichloro-1-oxo-2-{3-oxo-3-(1,3-thiazolidin-3-yl)propyl}methyl]-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 35 (8))

Melting point 218–220° C. Elemental analysis for C₂₈H₂₇N₃O₅Cl₂S ¼H₂OCalculated: C, 56.71; H, 4.67; N, 7.09. Found: C, 56.66; H, 4.58; N,6.92. ¹H-NMR(CDCl₃) δ: 0.99 (3H, t, J=7.2 Hz), 1.42–1.60 (2H, m),1.77–1.91 (2H, m), 2.80–2.94 (2H, m), 2.98 (2H, t, J=6.3 Hz), 3.60 (1H,t, J=6.2 Hz), 3.72 (1H, t, J=6.2 Hz), 3.95 (2H, t, J=6.3 Hz), 4.35–4.47(4H, m), 5.21 (2H, s), 7.71–7.86 (5H, m), 8.46 (1H, s).

(2)Tert-butyl{4-butoxy-6,7-dichloro-1-oxo-2-{(3-oxo-3-(1,3-thiazolidin-3-yl)propyl}-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 218–218.5° C. Elemental analysis for C₂₅H₃₃N₃O₅Cl₂SCalculated: C, 53.71; H, 5.96; N, 7.52. Found: C, 54.08; H, 6.20; N,7.35. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.3 Hz), 1.45 (9H, s), 1.51–1.63(2H, m), 1.80–1.94 (2H, m), 2.89–3.00 (2H, m), 3.06 (2H, t, J=6.2 Hz),3.69–3.91 (4H, m), 4.38 (2H, t, J=6.8 Hz), 4.46 (1H, s) 4.54 (1H, s),4.61 (2H, d, J=5.6 Hz), 5.40 (1H, bs), 7.79 (1H, s), 8.45 (1H, s).

(3)3-(Aminomethyl)-4-butoxy-6,7-dichloro-2-{3-oxo-3-(1,3-thiazolidin-3-yl)propyl}-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 206–207° C. Elemental analysis for C₂₀H₂₆N₃O₃Cl₃SCalculated: C, 48.54; H, 5.30; N, 8.49. Found: C, 48.19; H, 5.19; N,8.36. ¹H-NMR(DMSO-d₆) δ: 0.99 (3H, t, J=7.3 Hz), 1.45–1.64 (2H, m),1.78–1.92 (2H, m), 2.84 (2H, bs), 2.97 (1H, t, J=6.2 Hz), 3.06 (1H, t,J=6.2 Hz), 3.46 (2H, s), 3.65 (2H, q, J=6.2 Hz), 3.93 (2H, t, J=6.4 Hz),4.27 (2H, d, J=6.6 Hz), 4.44 (1H, s), 4.50 (1H, s), 7.92 (1H, s), 8.38(1H, s), 8.66 (3H, bs).

Example 44(2S)-1-[3-[3-(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl]propanoyl]-2-pyrrolidinecarboxamidehydrochloride

(1)(2S)-1-[3-[4-Butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)-isoquinolinyl]propanoyl]-2-pyrrolidinecarboxamide(synthesized according to the method similar to that in Example 35 (8))

Melting point 235–236.5° C. Elemental analysis for C₃₀H₃₀N₄O₆Cl₂ ½H₂OCalculated: C, 57.88; H, 5.02; N, 9.00. Found: C, 57.86; H, 4.94; N,8.90. ¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.3 Hz), 1.43.–1.62 (2H, m),1.69–1.99 (4H, m), 2.33–2.42 (1H, m), 2.67–2.89 (2H, m), 3.22–3.29 (2H,m), 3.98 (2H, t, J=,6.6 Hz), 4.35–4.49 (2H, m), 5.16 (2H, d, J=2.2 Hz),5.37 (1H, bs), 7.06 (1H, bs), 7.72–7.86 (5H, m), 8.44 (1H, s).

(2)Tert-butyl(2-{3-[(2S)-2-(aminocarbonyl)pyrrolizinyl]-3-oxopropyl}-4-butoxy-6,7-dichloro-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 159–160° C. Elemental analysis for C₂₆H₃₅N₃O₅Cl₂Calculated: C, 57.78; H, 6.53; N, 7.77. Found: C, 57.95; H, 6.43; N,7.60. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.2 Hz), 1.43,(9H, s), 1.53–1.73(4H, m), 1.83–2.00 (4H, m), 2.33–2.42 (1H, m), 2.79–2.98 (2H, m),3.37–3.65 (2H, m), 3.87 (2H, t, J=6.5 Hz), 4.24–4.44 (2H, m), 4.55 (2H,d, J=6.4 Hz), 5.34 (1H, bs), 5.41 (11H, bs), 7.13 (1H, bs), 7.79 (1H,s), 8.42 (1H, s).

(3)(2S)-1-[3-[3-(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl]propanoyl]-2-pyrrolidinecarboxamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 185–185.5° C. Elemental analysis for C₂₂H₂₉N₄O₄Cl₃ ½H₂OCalculated: C, 49.96; H, 5.72; N, 10.59. Found: C, 50.12; H, 5.79; N,10.29. ¹H-NMR(DMSO-d₆) δ: 1.00 (3H, t, J=7.3 Hz), 1.45–1.64 (2H, m),1.72–1.99 (5H, m), 2.65–2.83 (2H, m), 3.33–3.55 (4H, m), 3.93 (2H, t,J=6.4 Hz), 4.08–4.28 (4H, m), 6.94 (1H, bs), 7.35 (1H, bs), 7.92 (1H,s), 8.38 (1H, s), 8.72 (3H, bs).

Example 45(2S)-1-[3-[3-(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl]propanoyl]-2-pyrrolidinecarbonitrile hydrochloride

(1) A solution oftert-butyl(2-{3-[(2S)-2-(aminocarbonyl)pyrrolizinyl]-3-oxopropyl}-4-butoxy-6,7-dichloro-1-oxo-1,2-dihydro-3-isoquinolinyl)-methylcarbamate(Example 44 (1)) (0.58 g, 1 mmol) and cyanuric chloride (0.54 g, 3 mmol)in N,N-dimethylformamide (50 mmol) was stirred at 0° C. for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasrecrystallized from tetrahydrofuran diisopropyl ether to give tert-butyl(4-butoxy-6,7-dichloro-2-{3-[(2S)-2-cyanopyrrolizinyl]-3-oxopropyl}-1oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.39 g, 69.6%) as crystals.

Melting point 181–183° C. Elemental analysis C₂₇H₃₄N₄O₅Cl₂ Calculated:C, 57.35; H, 6.06; N, 9.91. Found: C, 57.16; H, 6.24; N, 9.61.¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.4 Hz), 1.45 (9H, s), 1.51–1.63 (2H,m), 1.76–1.94 (2H, m), 2.11–2.32 (4H, m), 2.91 (2H, t, J=6.8 Hz),3.44–3.51 (1H, m), 3.62–3.67, (1H, m), 3.88 (2H, t, J=6.6 Hz), 4.40 (2H,t, J=6.8 Hz), 4.61 (2H, d, J=5.6 Hz), 4.63–4.72 (1H, m), 5.38 (1H, s),7.79 (1H, s), 8.44 (1H, s).

(2)(2S)-1-[3-[3-(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl]propanoyl]-2-pyrrolidinecarbonitrile hydrochloride (synthesized according to the method similarto that in Example 1 (7))

¹H-NMR(DMSO-d₆) δ: 0.99 (3H, t, J=7.3 Hz), 1.47–1.64 (2H, m), 1.71–2.19(6H, m), 2.78–2.88 (2H, m), 3.36–3.82 (2H, m), 3.93 (2H, t, J=6.4 Hz),4.16–4.58 (5H, m), 7.93 (1H, s), 8.38 (1H, s), 8.64 (3H, bs).

Example 46 3-(Aminomethyl)-4-butoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 72–72.5° C. Elemental analysis for C₁₇H₂₁NO₄ ¼H₂OCalculated: C, 66.32; H, 7.04; N, 4.55. Found: C, 66.40; H, 7.14; N,4.54. ¹H-NMR(CDCl₃) δ: 0.85 (9H, s), 1.47 (3H, t, J=7.2 Hz), 4.48 (2H,q, J=7.2 Hz), 4.54 (2H, bs), 7.69–7.80 (2H, m), 8.13–8.18 (1H, m),8.44–8.749 (1H, m), 10.85 (1H, s).

(2) Ethyl4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.01 (3H, t, J=7.3 Hz), 1.44 (3H, t,J=7.2 Hz), 1.44–1.60 (2H, m), 1.74–1.84 (2H, m), 3.96 (2H, t, J=6.6 Hz),4.11 (2H, bs), 4.43 (2H, q, J=7.2 Hz), 7.51–7.61 (1H, m), 7.68–7.81 (2H,m), 8.43–8.47 (1H, m).

(3) 4-Butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid(synthesized according to the method similar to that in Example 4 (3))

Melting point 146–148° C. ¹H-NMR(CDCl₃) δ: 0.96 (9H, s), 1.00 (3H, t,J=7.4 Hz), 1.46–1.65 (2H, m), 1.76–1.90 (2H, m), 4.01 (2H, t, J=6.6 Hz),4.19 (2H, bs), 5.71 (1H, bs), 7.51–7.60 (1H, m), 7.67–7.86 (2H, m),8.41–8.45 (1H, m).

(4) 4-Butoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 123–124° C. Elemental analysis for C₁₉H₂₇NO₃ Calculated:C, 70.89; H, 8.61; N, 4.35. Found: C, 71.29; H, 8.23; N, 4.36.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.07 (3H, t, J=7.3 Hz), 1.50–1.68 (2H,m), 1.80–1.94 (2H, m), 2.35 (1H, bs), 3.91 (2H, t, J=6.4 Hz), 4.22 (2H,bs), 4.89 (2H, bs), 7.42–7.50 (1H, m), 7.60–7.72 (2H, m), 8.35 (1H, d,J=8.1 Hz).

(5) 4-Butoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.1 Hz), 1.52–1.69 (2H,m), 1.82–1.96 (2H, m), 3.96 (2H, t, J=6.6 Hz), 4.18 (2H bs), 4.90 (2H,bs), 7.50–7.58 (1H, m), 7.66–7.78 (2H, m), 8.42–8.46 (1H, m).

(6)2-{(4-Butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in

Example 4 (6))

Melting point 132.5–133° C. Elemental analysis for C₂₇H₃₀N₂O₄ ¼H₂OCalculated: C, 71.90; H, 6.82; N, 6.21. Found: C, 72.18; H, 6.73; N,6.12. ¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.3 Hz), 1.01 (9H, s), 1.45–1.60(2H, m), 1.82–1.96 (2H, m), 4.03 (2H, t, J=6.8 Hz), 4.14 (2H, bs), 5.09(2H, s), 7.46–7.54 (1H, m), 7.64–7.83 (6H, m), 8.39–8.43 (1H, m).

(7)Tert-butyl(4-butoxy-2neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 138–139° C. Elemental analysis for C₂₄H₃₆N₂O₄ Calculated:C, 69.20; H, 8.71; N, 6.73. Found: C, 69.30; H, 8.80; N, 6.70.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.03 (3H, t, J=7.4 Hz), 1.45 (9H, s),1.53–1.65 (2H, m), 1.76–1.94 (2H, m), 3.87 (2H, t, J=6.6 Hz), 4.14 (2H,bs), 4.58 (2H, d, J=5.2 Hz), 4.66 (1H, bs), 7.46–7.54 (1H, m), 7.64–7.73(2H, m), 8.40–8.44 (1H, m).

(8) 3-(Aminomethyl)-4-butoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 231–232° C. Elemental analysis for C₁₉H₂₉N₂O₂ClCalculated: C, 64.67; H, 8.28; N, 7.94. Found: C, 64.61; H, 8.44; N,7.76. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 0.99 (3H, t, J=7.3 Hz), 1.48–1.62(2H, m), 1.78–1.92 (2H, m), 3.94 (2H, t, J=6.4 Hz), 4.11 (2H, bs), 4.25(2H, bs), 7.58–7.67 (1H, m), 7.77–7.90 (2H, m), 8.27–8.30 (1H, m), 8.59(3H, bs).

Example 473-(Aminomethyl)-4-butoxy-6,7-dichloro-2-(2-furylmethyl)-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6,7-dichloro-2-(2-furylmethyl)-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 134–135° C. Elemental analysis for C₁₇H₁₃NO₅Cl₂calculated: C, 53.42; H, 3.43; N, 3.66. Found: C, 53.84; H, 3.53; N,3.44. ¹H-NMR(CDCl₃) δ: 1.42 (3H, t, J=7.2 Hz), 4.42 (2H, q, J=7.2 Hz),5.68 (2H, s), 6.16 (1H, dd, J=0.8, 3.1 Hz), 6.27 (1H, dd, J=2.0, 3.1Hz), 7.28 (1H, dd, J=0.8, 2.0 Hz), 8.21 (1H, s), 8.54 (1H, s), 11.11(1H, s).

(2) Ethyl4-butoxy-6,7-dichloro-2-(2-furylmethyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.4 Hz), 1.37 (3H, t, J=7.1 Hz),1.42–1.61 (2H, m), 1.71–1.85 (2H, m), 3.92 (2H, t, J=6.4 Hz), 4.39 (2H,q, J=7.1 Hz), 5.36 (2H, s), 6.28–6.32 (2H, m), 7.32 (1H, d, J=1.5 Hz),7.81 (1H, s), 8.53 (1H, s).

(3)4-Butoxy-6,7-dichloro-2-(2-furylmethyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 147.5–148° C. Elemental analysis for C₁₉H₁₇NO₅Cl₂Calculated: C, 57.59; H, 4.83; N, 3.53. Found: C, 57.40; H, 4.79; N,3.37. ¹H-NMR(CDCl₃) δ: 0.99 (3H, t, J=7.3 Hz), 1.47–1.62 (2H, m),1.75–1.89 (2H, m), 4.00 (2H, t, J=6.6 Hz), 5.16 (1H, bs), 5.52 (2H, s),6.28 (1H, dd, J=1.8, 3.2 Hz), 6.35 (1H, dd, J=0.8, 3.2 Hz), 7.30 (1H,dd, J=0.8, 1.8 Hz), 7.82 (1H, s), 8.54 (1H, s).

(4)4-Butoxy-6,7-dichloro-2-(2-furylmethyl)-3-hydroxymethyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 120–121° C. Elemental analysis for C₁₉H₁₉NO₅Cl₂Calculated: C, 57.59; H, 4.83; N, 3.53. Found: C, 57.40; H, 4.79; N,3.37. ¹H-NMR(CDCl₃) δ: 1.04 (3H, t, J=7.3 Hz), 1.49–1.62 (2H, m),1.78–1.92 (2H, m), 3.88 (2H, t, J=6.5 Hz), 4.97 (2H, d, J=5.4 Hz), 5.49(2H, s), 6.32 (1H, dd, J=1.8, 2.9 Hz), 6.40 (1H, dd, J=0.8, 2.9 Hz),7.31 (1H, dd, J=0.8, 1.8 Hz), 7.75 (1H, s), 8.45 (1H, s).

(5)4-Butoxy-3-chloromethyl-6,7-dichloro-2-(2-furylmethyl)-1(2H)-isoquinoline(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.05 (3H, t, J=7.3 Hz), 1.55–1.79 (2H, m), 1.82–1.93(2H, m), 3.99 (2H, t, J=6.6 Hz), 5.00 (2H, s), 5.46 (2H, s), 6.31 (1H,dd, J=1.9, 3.2 Hz), 6.41 (1H, dd, J=1.1, 3.2 Hz), 7.31 (1H, dd, J=1.1,1.9 Hz), 7.81 (1H, s), 8.51 (1H, s).

(6)2-{(4-Butoxy-6,7-dichloro-2-(2-furylmethyl)-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 148–149° C. Elemental analysis for C₂₇H₂₂N₂O₅Cl₂Calculated: C, 61.72; H, 4.22; N, 5.33. Found: C, 61.95; H, 4.51; N,5.47. ¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.3 Hz), 1.45–1.63 (2H, m),1.80–1.94 (2H, m), 4.02 (2H, t, J=6.8 Hz), 5.15 (2H, s), 5.36 (2H, s),6.05 (1H, dd, J=1.8, 3.2 Hz), 6.17 (1H, dd, J=0.8, 3.2 Hz), 6.89 (1H,dd, J=0.8, 1.8 Hz), 7.69–7.80 (4H, bs), 7.82 (1H, s), 8.49 (1H, s).

(7)Tert-butyl(4-butoxy-6,7-dichloro-2-(2-furylmethyl)-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 143–144° C. Elemental analysis for C₂₄H₂₈N₂O₅Cl₂Calculated: C, 58.19; H, 5.70; N, 5.65. Found: C, 58.31; H, 5.53; N,5.70. ¹H-NMR(CDCl₃) δ: 1.04 (3H, t, J=7.3 Hz), 1.46 (9H, s), 1.51–1.67(2H, m), 1.79–1.93 (2H, m), 3.84 (2H, t, J=6.5 Hz), 4.66 (2H, d, J=5.8Hz), 4.91 (1H, bs), 5.37 (2H, s), 6.30 (1H, dd, J=2.0, 3.4 Hz), 6.44(1H, d, J=3.4 Hz), 7.32 (1H, d, J=2.0 Hz), 7.75 (1H, s), 8.47 (1H, s).

(8)3-(Aminomethyl)-4-butoxy-6,7-dichloro-2-(2-furylmethyl)-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 223–224° C. Elemental analysis for C₁₉H₂₁N₂O₃Cl₃Calculated: C, 52.86; H, 4.90; N, 6.49. Found: C, 52.55; H, 4.97; N,6.58. ¹H-NMR(DMSO-d₆) δ: 0.99 (3H, t, J=7.3 Hz), 1.44–1.63 (2H, m),1.77–1.92 (2H, m), 3.94 (2H, t, J=6.4 Hz), 4.26 (2H, s), 5.40 (2H, s),6.42 (1H, dd, J=1.8, 3.2 Hz), 6.45 (1H, dd, J=1.0, 3.2 Hz), 7.61 (1H,dd, J=1.0, 1.8 Hz), 7.93 (1H, s) 8.39 (1H, s), 8.82 (3H, bs).

Example 483-(Aminomethyl)-4-butoxy-6,7-dichloro-2-(2methoxyethyl)-1(2H)-isoquinolinonehydrochloride

(1) ethyl6,7-dichloro-4-hydroxy-2-(2methoxyethyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 110.5–111° C. Elemental analysis for C₁₅H₁₅NO₅Cl₂Calculated: C, 50.02; H, 4.20; N, 3.89. Found: C, 49.86; H, 4.44; N,3.76. ¹H-NMR(CDCl₃) δ: 1.46 (3H, t, J=7.1 Hz), 3.30 (3H, s), 3.62 (2H,d, J=5.8 Hz), 4.49 (2H, q, J=7.1 Hz), 4.61 (2H, t, J=5.8 Hz), 8.22 (1H,s), 8.51 (1H, s), 10.95 (1H, s).

(2) Ethyl4-butoxy-6,7-dichloro-2-(2-methoxyethyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

Melting point 102–103° C. Elemental analysis for C₁₉H₂₃NO₅Cl₂Calculated: C, 54.82; H, 5.57; N, 3.36. Found: C, 54.81; H, 5.35; N,3.36. ¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.3 Hz), 1.44 (3H, t, J=7.2 Hz),1.50–1.62 (2H, m), 1.72–1.86 (2H, m), 3.31 (3H, s), 3.63 (2H, t, J=5.9Hz), 3.94 (2H, t, J=6.4 Hz), 4.26 (2H, t, J=5.9 Hz), 4.45 (2H, q, J=7.2Hz), 7.82 (1H, s), 8.50 (1H, s).

(3)4-Butoxy-6,7-dichloro-2-(2-methoxyethyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 142–143° C. Elemental analysis for C₁₇H₁₉NO₅Cl₂Calculated: C, 52.59; H, 4.93; N, 3.61. Found: C, 52.58; H, 4.94; N,3.41. ¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.2 Hz), 1.44–1.63 (2H, m),1.74–1.89 (2H, m), 3.41 (3H, s), 3.85 (2H, t, J=5.3 Hz), 4.00 (2H, t,J=6.4 Hz), 4.37–4.40 (2H, m), 7.82 (1H, s), 8.48 (1H, s).

(4)4-Butoxy-6,7-dichloro-3-hydroxymethyl-2-(2-methoxyethyl)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 122–123° C. Elemental analysis for C₁₇H₂₁NO₄Cl₂Calculated: C, 54.56; H, 5.66; N, 3.74. Found: C, 54.34; H, 5.59; N,3.57. ¹H-NMR(CDCl₃) δ: 1.04 (3H, t, J=7.3 Hz), 1.50–1.69 (2H, m),1.80–1.94 (2H, m), 3.34 (3H, s), 3.83 (2H, t, J=5.5 Hz), 3.96 (2H, t,J=6.6 Hz), 4.38 (2H, t, J=5.5 Hz), 4.46 (1H, t, J=6.4 Hz), 4.79 (2H, d,J=6.4 Hz), 7.84 (1H, s), 8.47 (1H, s).

(5)4-Butoxy-3-chloromethyl-6,7-dichloro-2-(2-methoxyethyl)-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.05 (3H, t, J=7.3 Hz), 1.55–1.70 (2H, m), 1.82–1.96(2H, m), 3.26 (3H, s), 3.69 (2H, t, J=4.8 Hz), 3.98 (2H, t, J=6.4 Hz),4.43 (2H, t, J=4.8 Hz), 4.99 (2H, s), 7.82 (1H, s), 8.50 (1H, s).

(6)2-{(4-Butoxy-6,7-dichloro-2-(2-methoxyethyl)-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 151–152° C. Elemental analysis for C₂₅H₂₄N₂O₅Cl₂Calculated: C, 59.65; H, 4.81; N, 5.57. Found: C, 59.52; H, 4.85; N,5.55. ¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.3 Hz), 1.44–1.62 (2H, m),1.79–1.93 (2H, m), 2.97 (3H, s), 3.64 (2H, t, J=4.9 Hz), 3.98 (2H, t,J=6.6 Hz), 4.37 (2H, t, J=4.9 Hz), 5.10 (2H, s), 7.68–7.87 (5H, m), 8.47(1H, s).

(7)Tert-butyl{4-butoxy-6,7-dichloro-2-(2-methoxyethyl)-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 137–138° C. Elemental analysis for C₂₂H₃₀N₂O₅Cl₂Calculated: C, 55.82; H, 6.39; N, 5.92. Found: C, 55.99; H, 6.33; N,5.76. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.3 Hz), 1.46 (9H, s), 1.51–1.64(2H, m), 1.81–1.95 (2H, m), 3.33 (3H, s), 3.80 (2H, t, J=4.5 Hz), 3.85(2H, t, J=6.6 Hz), 4.30 (2H, t, J=4.5 Hz), 4.54 (2H, d, J=5.2 Hz), 6.15(1H, bs), 7.80 (1H, s), 8.46 (1H, s).

(8)3-(Aminomethyl)-4-butoxy-6,7-dichloro-2-(2-methoxyethyl)-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 241.5–242° C. Elemental analysis for C₁₇H₂₃N₂O₃Cl₃Calculated: C, 49.83; H, 5.66; N, 6.84. Found: C, 49.80; H, 5.91; N,6.81. ¹H-NMR(DMSO-d₆) δ: 0.99 (3H, t, J=7.3 Hz), 1.45–1.63 (2H, m),1.77–1.91 (2H, m), 3.24 (3H, s), 3.61 (2H, d, J=4.9 Hz), 3.93 (2H, t,J=6.6 Hz), 4.23–4.32 (4H, m), 7.91 (1H, s), 8.38 (1H, s), 8.68 (3H, bs).

Example 493-(Aminomethyl)-4-(2-methoxyethoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl4-(2-methoxyethoxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.43 (3H, t, J=7.2 Hz), 3.48 (3H, s),3.71–3.75 (2H, m), 4.07–4.17 (2H, m), 4.43 (2H, q, J=7.2 Hz), 7.53–7.61(1H, m), 7.69–7.77 (1H, m), 7.93–7.97 (1H, m), 8.42–8.47 (1H, m).

(2)4-(2-Methoxyethoxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 148–149° C. Elemental analysis for C₁₈H₂₃NO₅ Calculated:C, 64.85; H, 6.95; N, 4.20. Found: C, 64.79; H, 6.96; N, 4.09.¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 3.49 (3H, s), 3.76–3.81 (2H, m),4.27–4.32 (4H, m), 7.56–7.64 (1H, m), 7.70–7.78 (1H, m), 7.89 (1H, dd,J=0.8, 8.0 Hz), 8.44 (1H, dd, J=1.0, 8.0 Hz), 9.79 (1H, bs).

(3) 3-Hydroxymethyl-4-(2-methoxyethoxy)-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 145–145.5° C. Elemental analysis for C₁₈H₂₅NO₄ Calculated:C, 67.69; H, 7.89; N, 4.39. Found: C, 67.54; H, 8.06; N, 4.28.¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 3.45 (3H, s), 3.58 (1H, t, J=6.8 Hz),3.75–3.79 (2H, m), 4.14–4.18 (2H, m), 4.23 (2H, bs), 4.90 (2H, bs),7.44–7.52 (1H, m), 7.63–7.76 (2H, m), 8.40 (1H, dd, J=0.8, 8.0 Hz).

(4) 3-Chloromethyl-4-(2-methoxyethoxy)-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 3.52 (3H, s), 3.76–3.82 (2H, m),4.11–4.18 (2H, m), 4.21 (2H, bs), 4.96 (2H, bs), 7.50–7.58 (1H, m),7.67–7.76 (1H, m), 7.87 (1H, dd, J=0.8, 8.0 Hz), 8.44 (1H, dd, J=0.8,8.0 Hz).

(5)2-{{4-(2-Methoxyethoxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 145–146° C. Elemental analysis for C₂₆H₂₈N₂O₅ Calculated:C, 68.93; H, 6.34; N, 6.18. Found: C, 69.07; H, 6.06; N, 6.53.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 3.47 (3H, s), 3.78–3.82 (2H, m),4.24–4.29 (2H, m), 4.31 (2H, bs), 5.12 (2H, bs), 7.45–7.54 (1H, m),7.65–7.92 (6H, m), 8.41 (1H, dd, J=0.7, 8.1 Hz).

(6)Tert-butyl{4-(2-methoxyethoxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 143–144° C. Elemental analysis for C₂₃H₃₄N₂O₅ Calculated:C, 66.06; H, 8.19; N, 6.69. Found: C, 65.73; H, 8.14; N, 6.78.¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.44 (9H, s), 3.48 (3H, s), 3.74–3.79(2H, m), 4.07–4.12 (2H, m), 4.19 (2H, bs), 4.61 (2H, d, J=6.0 Hz), 5.17(1H, bs), 7.46–7.54 (1H, m), 7.65–7.73 (1H, m), 7.79 (1H, d, J=8.2 Hz),8.42 (1H, dd, J=0.7, 8.2 Hz).

(7) 3-(Aminomethyl)-4-(2-methoxyethoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 205–206° C. Elemental analysis for C₁₈H₂₇N₂O₃Cl ¼H₂OCalculated: C, 60.16; H, 7.71; N, 7.80. Found: C, 59.84; H, 7.52; N,7.82. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 1.10 (6H, d, J=6.6 Hz), 2.14–2.27(1H, m), 3.73 (2H, d, J=6.6 Hz), 4.11 (2H, bs), 4.24 (2H, s), 7.89 (1H,s), 8.38 (1H, s), 8.63 (3H, bs).

Example 503-(Aminomethyl)-4-butoxy-7-methyl-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl4-hydroxy-7-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 90–91° C. Elemental analysis for C₁₈H₂₃NO₄ Calculated: C,68.12; H, 7.30; N, 4.41. Found: C, 67.98; H, 7.10; N, 4.22.¹H-NMR(CDCl₃) δ: 0.84 (9H, s), 1.46 (3H, t, J=7.1 Hz), 2.54 (3H, s),4.42 (2H, bs), 4.49 (2H, q, J=7.1 Hz), 7.57 (1H, dd, J=1.9, 8.0 Hz),8.04 (1H, d, J=8.0 Hz), 8.26 (1H, d, J=1.9 Hz), 10.90 (1H, s).

(2) Ethyl4-butoxy-7-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR (CDCl₃) δ: 0.93 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.44 (3H, t,J=7.0 Hz), 1.47–1.62 (2H, m), 1.73–1.87 (2H, m), 2.51 (3H, s), 3.95 (2H,t, J=6.6 Hz), 4.11 (2H, bs), 4.42 (2H, q, J=7.0 Hz), 7.54 (1H, dd,J=1.7, 8.0 Hz), 7.68 (1H, d, J=8.0 Hz), 8.26 (1H, d, J=1.7 Hz).

(3)4-Butoxy-7-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 160.5–161° C. Elemental analysis for C₂₀H₂₇NO₄ Calculated:C, 69.54; H, 7.88; N, 4.05. Found: C, 69.45; H, 8.10; N, 3.98.¹H-NMR(CDCl₃) δ: 0.91 (9H, s), 0.99 (3H, t, J=7.1 Hz), 1.44–1.63 (2H,m), 1.76–1.90 (2H, m), 2.50 (3H, s), 4.00 (2H, t, J=6.6 Hz), 4.26 (2H,bs), 5.92 (1H, bs), 7.45–7.56 (2H, m), 8.13 (1H, s).

(4) 4-Butoxy-3-hydroxymethyl-7-methyl-2-neopentyl-1(2H)-isoquinoline(synthesized according to the method similar to that in Example 4 (4))

Melting point 109–110° C. Elemental analysis for C₂₀H₂₉NO₃ Calculated:C, 72.47; H, 8.82; N, 4.23. Found: C, 72.18; H, 8.75; N, 4.26.¹H-NMR(CDCl₃) δ: 0.96 (9H, s), 1.03 (3H, t, J=7.4 Hz), 1.49–1.68 (2H,m), 1.79–1.93 (2H, m), 2.45 (3H, s), 2.61 (1H, bs), 3.90 (2H, t, J=6.6Hz), 4.22 (2H, bs), 4.87 (2H, bs), 7.43 (1H, dd, J=1.8, 8.0 Hz), 7.56(1H, d, J=8.0 Hz), 8.09 (1H, d, J=1.8 Hz).

(5) 4-Butoxy-3-chloromethyl-7-methyl-2-neopentyl-1(2H)-isoquinoline(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.04 (3H, t, J=7.3 Hz), 1.51–1.69 (2H,m), 1.81–1.95 (2H, m), 2.50 (3H, s), 3.95 (2H, t, J=6.4 Hz), 4.18 (2H,bs), 4.90 (2H, bs), 7.52 (1H, dd, J=1.8, 8.1 Hz), 7.65 (1H, d, J=8.1Hz), 8.24 (1H, d, J=1.8 Hz).

(6)2-{(4-Butoxy-7-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 174–175° C. Elemental analysis for C₂₈H₃₂N₂O₄ ¼H₂OCalculated: C, 72.31; H, 7.04; N, 6.02. Found: C, 72.57; H, 7.35; N,6.04. ¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.01 (3H, t, J=7.3 Hz), 1.44–1.59(2H, m), 1.81–1.95 (2H, m), 2.48 (3H, s), 4.02 (2H, t, J=6.8 Hz), 4.10(2H, bs), 5.08 (2H, s), 7.50 (1H, dd, J=1.7, 8.3 Hz), 7.63–7.82 (5H, m),8.22 (1H, d, J=1.7 Hz).

(7)Tert-butyl(4-butoxy-7-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 153–154° C. Elemental analysis for C₂₅H₃₈N₂O₄ Calculated:C, 69.74; H, 8.90; N, 6.51. Found: C, 69.65; H, 9.13; N, 6.56.¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.03 (3H, t, J=7.2 Hz), 1.45 (9H, s),1.52–1.63 (2H, m), 1.79–1.93 (2H, m), 2.49 (3H, s), 3.86 (2H, t, J=6.5Hz), 4.18 (2H, bs), 4.56 (2H, t, J=5.4 Hz), 4.68 (1H, bs), 7.50 (1H, dd,J=1.8, 8.0 Hz), 7.60 (1H, d, J=8.0 Hz), 8.21 (1H, d, J=1.8 Hz).

(8) 3-(Aminomethyl)-4-butoxy-7-methyl-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to thatin-Example 1 (7))

Melting point 231–233° C. Elemental analysis for C₂₀H₃₁N₂O₂ClCalculated: C, 65.47; H, 8.52; N, 7.63. Found: C, 65.44; H, 8.53; N,7.86. ¹H-NMR(DMSO-d₆) δ: 0.99 (9H, s), 0.99 (3H, t, J=7.2 Hz), 1.45–1.64(2H, m), 1.77–1.91 (2H, m), 2.47 (3H, s), 3.92 (2H, t, J=6.6 Hz), 4.10(2H, bs), 4.23 (2H, d, J=5.2 Hz), 7.63–7.72 (2H, m), 8.09 (1H, s), 8.56(3H, bs).

Example 513-(Aminomethyl)-4-butoxy-6-methyl-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl4-hydroxy-6-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

¹H-NMR(CDCl₃) δ: 0.84 (9H, s), 1.46 (3H, t, J=7.2 Hz), 2.54 (3H, s),4.42 (2H, bs), 4.47 (2H, q, J=7.2 Hz), 7.51 (1H, dd, J=1.9, 8.0 Hz),7.93 (1H, d, J=1.9 Hz), 8.33 (1H, d, J=8.0 Hz), 10.86 (1H, s).

(2) Ethyl4-butoxy-6-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.00 (3H, t, J=7.2 Hz), 1.44 (3H, t,J=7.2 Hz), 1.47–1.60 (2H, m), 1.74–1.91 (2H, m), 2.52 (3H, s), 3.96 (2H,t, J=6.4 Hz), 4.07 (2H, bs), 4.43 (2H, q, J=7.2 Hz), 7.38 (1H, dd,J=1.0, 8.0 Hz), 7.68 (1H, d, J=1.0 Hz), 8.26 (1H, d, J=8.0 Hz).

(3)4-Butoxy-6-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 153–154° C. Elemental analysis for C₂₀H₂₇NO₄ Calculated:C, 69.54; H, 7.88; N, 4.05. Found: C, 69.59; H, 8.16; N, 4.06.¹H-NMR(CDCl₃) δ: 0.91 (9H, s), 1.01 (3H, t, J=7.1 Hz), 1.48–1.65 (2H,m), 1.77–1.88 (2H, m), 2.52 (3H, s), 4.02 (2H, t, J=6.4 Hz), 4.22 (2H,bs), 6.42 (1H, bs), 7.38 (1H, dd, J=1.3, 8.2 Hz), 7.45 (1H, d, J=1.3Hz), 8.25 (1H, d, J=8.2 Hz).

(4) 4-Butoxy-3-hydroxymethyl-6-methyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 133–134° C. Elemental analysis for C₂₀H₂₉NO₃ Calculated:C, 72.47; H, 8.82; N, 4.23. Found: C, 72.43; H, 8.80; N, 4.24.¹H-NMR(CDCl₃) δ: 0.97 (9H, s), 1.04 (3H, t, J=7.2 Hz), 1.51–1.69 (2H,m), 1.80–1.94 (2H, m), 2.38 (1H, bs), 2.49 (3H, s), 3.90 (2H, t, J=6.6Hz), 4.20 (2H, bs), 4.86 (2H, bs), 7.27 (1H, dd, J=1.6, 8.0 Hz), 7.45(1H, d, J=1.6 Hz), 8.22 (1H, d, J=8.0 Hz).

(5) 4-Butoxy-3-chloromethyl-6-methyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.05 (3H, t, J=7.1 Hz), 1.56–1.71 (2H,m), 1.82–1.92 (2H, m), 2.52 (3H, s), 3.95 (2H, t, J=6.5 Hz), 4.14 (2H,bs), 4.88 (2H, bs), 7.35 (1H, dd, J=1.8, 8.0 Hz), 7.51 (1H, d, J=1.8Hz), 8.32 (1H, d, J=8.0 Hz).

(6)2-{(4-Butoxy-6-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 170–172° C. Elemental analysis for C₂₈H₃₂N₂O₄ Calculated:C, 73.02; H, 7.00; N, 6.08. Found: C, 72.72; H, 7.05; N, 6.25.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.01 (3H, t, J=7.2 Hz), 1.50–1.65 (2H,m), 1.82–1.93 (2H, m), 2.50 (3H, s), 4.03 (2H, t, J=6.8 Hz), 4.06 (2H,bs), 5.08 (2H, s), 7.31 (1H, dd, J=1.4, 8.2 Hz), 7.53 (1H, d, J=1.4 Hz),7.68–7.82 (4H, m), 8.29 (1H, d, J=8.2 Hz).

(7)Tert-butyl(4-butoxy-6-methyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 127–129° C. Elemental analysis for C₂₅H₃₈N₂O₄ Calculated:C, 69.74; H, 8.90; N, 6.51. Found: C, 69.80; H, 8.75; N, 6.46.¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.00 (3H, t, J=7.6 Hz), 1.45 (9H, s),1.53–1.68 (2H, m), 1.75–1.94 (2H, m), 2.51 (3H, s), 3.87 (2H, t, J=6.6Hz), 4.14 (2H, bs), 4.56 (2H, d, J=5.2 Hz), 4.65 (1H, bs), 7.32 (1H, dd,J=1.4, 8.4 Hz), 7.47 (1H, d, J=1.4 Hz), 8.30 (1H, d, J=8.4 Hz).

(8) 3-(Aminomethyl)-4-butoxy-6-methyl-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 201–203° C. Elemental analysis for C₂₀H₃₁N₂O₂ClCalculated: C, 65.47; H, 8.52; N, 7.63. Found: C, 65.50; H, 8.59; N,7.56. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.50–1.65(2H, m), 1.78–1.91 (2H, m), 2.50 (3H, s), 3.93 (2H, t, J=6.2 Hz), 4.09(2H, bs), 4.23 (2H, bs), 7.31 (1H, d, J=8.0 Hz), 7.55 (1H, s), 8.16 (1H,d, J=8.0 Hz), 8.58 (3H, bs).

Example 523-(Aminomethyl)-4-butoxy-2-neopentyl-7-trifluoromethyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl4-hydroxy-2-neopentyl-1-oxo-7-trifluoromethyl-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 133.5–134° C. Elemental analysis for C₁₈H₂₀NO₄F₃Calculated: C, 58.22; H, 5.43; N, 3.77. Found: C, 58.24; H, 5.48; N,3.76. ¹H-NMR(CDCl₃) δ: 0.86 (9H, s), 1.48 (3H, t, J=7.2 Hz), 4.45 (2H,bs), 4.50 (2H, q, J=7.2 Hz), 7.96 (1H, dd, J=1.8, 8.4 Hz), 8.27 (1H, d,J=8.4 Hz), 8.75 (1H, d, J=1.8 Hz), 10.71 (1H, s).

(2) Ethyl4-butoxy-2-neopentyl-1-oxo-7-trifluoromethyl-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 1.01 (3H, t, J=7.3 Hz), 1.45 (3H, t,J=7.1 Hz), 1.52–1.63 (2H, m), 1.74–1.88 (2H, m), 3.96 (2H, t, J=6.6 Hz),4.09 (2H, bs), 4.45 (2H, q, J=7.1 Hz), 7.90–7.94 (2H, m), 8.73–8.75 (1H,m).

(3)4-Butoxy-2-neopentyl-1-oxo-7-trifluoromethyl-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 169–170° C. Elemental analysis for C₂₀H₂₄NO₄F₃ Calculated:C, 60.14; H, 6.06; N, 3.51. Found: C, 60.17; H, 5.94; N, 3.45.¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 1.00 (3H, t, J=7.4 Hz), 1.45–1.64 (2H,m), 1.78–1.92 (2H, m), 4.03 (2H, t, J=6.6 Hz), 4.26 (2H, bs), 5.02 (1H,bs), 7.84–7.95 (2H, m), 8.70 (1H, s).

(4)4-Butoxy-3-hydroxymethyl-2-neopentyl-7-trifluoromethyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 98–99° C. Elemental analysis for C₂₀H₂₆NO₃F₃ ¼H₂OCalculated: C, 61.31; H, 6.85; N, 3.59. Found: C, 61.54; H, 6.83; N,3.79. ¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 1.05 (3H, t, J=7.3 Hz), 1.51–1.70(2H, m), 1.81–1.95 (2H, m), 3.02 (1H, bs), 3.91 (2H, t, J=6.4 Hz), 4.25(2H, bs), 4.89 (2H, bs), 7.70–7.75 (2H, m), 8.45 (1H, s).

(5)4-Butoxy-3-chloromethyl-2-neopentyl-7-trifluoromethyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.4 Hz), 1.52–1.76 (2H,m), 1.82–1.96 (2H, m), 3.95 (2H, t, J=6.4 Hz), 4.22 (2H, bs), 4.89 (2H,bs), 7.83–7.93 (2H, m), 8.72–8.74 (1H, m).

(6)2-{(4-Butoxy-2-neopentyl-1-oxo-7-trifluoromethyl-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 132–133° C. Elemental analysis for C₂₈H₂₉N₂O₄F₃Calculated: C, 65.36; H, 5.68; N, 5.44. Found: C, 65.34; H, 5.38; N,5.49. ¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.3 Hz), 1.02 (9H, s), 1.46–1.62(2H, m), 1.82–1.93 (2H, m), 4.02 (2H, t, J=6.8 Hz), 4.05 (2H, bs), 5.09(2H, s), 7.70–7.86 (6H, m), 8.70 (1H, s).

(7)Tert-butyl(4-butoxy-2-neopentyl-1-oxo-7-trifluoromethyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Elemental analysis for C₂₅H₃₅N₂O₄F₃ Calculated: C, 61.97; H, 7.28; N,5.78. Found: C, 61.86; H, 7.38; N, 5.73. ¹H-NMR(CDCl₃) δ: 1.00 (9H, s),1.04 (3H, t, J=7.4 Hz), 1.46 (9H, s), 1.53–1.68 (2H, m), 1.81–1.95 (2H,m), 3.87 (2H, t, J=6.6 Hz), 4.14 (2H, bs), 4.59 (2H, d, J=5.0 Hz), 4.82(1H, bs), 7.77–7.88 (2H, m), 8.66(1H, d, J=0.6 Hz).

(8)3-(Aminomethyl)-4-butoxy-2-neopentyl-7-trifluoromethyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 224–225° C. Elemental analysis for C₂₀H₂₈N₂O₂ClF₃Calculated: C, 57.07; H, 6.71; N, 6.66. Found: C, 56.77; H, 6.69; N,6.73. ¹H-NMR(DMSO-d₆) δ: 0.92 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.50–1.61(2H, m), 1.80–1.92 (2H, m), 3.96 (2H, t, J=6.4 Hz), 4.15 (2H, bs), 4.29(2H, bs), 8.00 (1H, d, J=8.4 Hz), 8.17 (1H, dd, J=1.8, 8.4 Hz), 8.52(1H, d, J=1.8 Hz), 8.66 (3H, bs).

Example 533-(Aminomethyl)-4-butoxy-2-neopentyl-6-trifluoromethyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl4-hydroxy-2-neopentyl-1-oxo-6-trifluoromethyl-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

¹H-NMR(CDCl₃) δ: 0.86 (9H, s), 1.49 (3H, t, J=7.2 Hz), 4.46 (2H, bs),4.51 (2H, q, J=7.2 Hz), 7.89 (1H, dd, J=2.0, 8.4 Hz), 8.43 (1H, d, J=2.0Hz), 8.57 (1H, d, J=8.4 Hz), 10.79 (1H, s).

(2) Ethyl4-butoxy-2-neopentyl-1-oxo-6-trifluoromethyl-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR (CDCl₃) δ: 0.95 (9H, s), 1.02 (3H, t, J=7.4 Hz), 1.45 (3H, t,J=7.1 Hz), 1.49–1.66 (2H, m), 1.76–1.90 (2H, m), 3.98 (2H, t, J=6.4 Hz),4.11 (2H, bs), 4.46 (2H, q, J=7.1 Hz), 7.78 (1H, dd, J=1.6, 8.4 Hz),8.05 (1H, d, J=1.6 Hz), 8.57 (1H, d, J=8.4 Hz).

(3)4-Butoxy-2-neopentyl-1-oxo-6-trifluoromethyl-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 164–166° C. Elemental analysis for C₂₀H₂₄NO₄F₃ Calculated:C, 60.14; H, 6.06; N, 3.51. Found: C, 60.15; H, 5.86; N, 3.43.¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 1.01 (3H, t, J=7.2 Hz), 1.48–1.66 (2H,m), 1.78–1.92 (2H, m), 4.04 (2H, t, J=6.4 Hz), 4.28 (2H, bs), 5.01 (1H,bs), 7.79 (1H, dd, J=1.4, 8.6 Hz), 8.00 (1H, d, J=1.4 Hz), 8.54 (1H, d,J=8.6 Hz).

(4)4-Butoxy-3-hydroxymethyl-2-neopentyl-6-trifluoromethyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 107–108° C. Elemental analysis for C₂₀H₂₆NO₃F₃ Calculated:C, 62.33; H, 6.80; N, 3.63. Found: C, 62.31; H, 6.74; N, 3.74.¹H-NMR(CDCl₃) δ: 0.97 (9H, s), 1.08 (3H, t, J=6.9 Hz), 1.52–1.71 (2H,m), 1.81–1.95 (2H, m), 2.48 (1H, bs), 3.91 (2H, t, J=6.4 Hz), 4.23 (2H,bs), 4.89 (2H, bs), 7.63 (1H, d, J=8.5 Hz), 7.94 (1H, s), 8.42 (1H, d,J=8.5 Hz).

(5)4-Butoxy-3-chloromethyl-2-neopentyl-6-trifluoromethyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.05 (3H, t, J=7.3 Hz), 1.54–1.72 (2H,m), 1.83–1.97 (2H, m), 3.96 (2H, t, J=6.4 Hz), 4.22 (2H, bs), 4.89 (2H,bs), 7.74 (1H, dd, J=1.6, 8.6 Hz), 8.02 (1H, d, J=1.6 Hz), 8.55 (1H, d,J=8.6 Hz).

(6)2-{(4-Butoxy-2-neopentyl-1-oxo-6-trifluoromethyl-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 123–124° C. Elemental analysis for C₂₈H₂₉N₂O₄F₃Calculated: C, 65.36; H, 5.68; N, 5.44. Found: C, 65.44; H, 5.77; N,5.48. ¹H-NMR(CDCl₃) δ: 1.01 (9H, s), 1.02 (3H, t, J=7.3 Hz), 1.48–1.67(2H, m), 1.83–1.97 (2H, m), 4.04 (2H, t, J=6.6 Hz), 4.07 (2H, bs), 5.09(2H, s), 7.67–7.84 (5H, m), 8.03 (1H, s), 8.52 (1H, d, J=8.4 Hz).

(7)Tert-butyl(4-butoxy-2-neopentyl-1-oxo-6-trifluoromethyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 153–154° C. Elemental analysis for C₂₅H₃₅N₂O₄F₃Calculated: C, 61.97; H, 7.28; N, 5.78. Found: C, 61.71; H, 7.09; N,5.75. ¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.04 (3H, t, J=7.4 Hz), 1.45 (9H,s), 1.51–1.70 (2H, m), 1.81–1.95 (2H, m), 3.88 (2H, t, J=6.4 Hz), 4.14(2H, bs), 4.59 (2H, d, J=5.8 Hz), 4.73 (1H, bs), 7.69 (1H, dd, J=1.6,8.2 Hz), 7.96 (1H, d, J=1.6 Hz), 8.52 (1H, d, J=8.2 Hz).

(8)3-(Aminomethyl)-4-butoxy-2-neopentyl-6-trifluoromethyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 206–208° C. Elemental analysis for C₂₀H₂₈N₂O₂ClF₃ ½H₂OCalculated: C, 55.88; H, 6.80; N, 6.52. Found: C, 55.71; H, 6.58; N,6.19. ¹H-NMR(DMSO-d₆) δ: 0.92 (9H, s), 1.00 (3H, t, J=7.4 Hz), 1.52–1.64(2H, m), 1.78–1.92 (2H, m), 3.97 (2H, t, J=6.5 Hz), 4.14 (2H, bs), 4.29(2H, bs), 7.94 (1H, d, J=8.6 Hz), 8.00 (1H, s), 8.49 (1H, d, J=8.6 Hz),8.61 (3H, bs).

Example 54 Methyl3-{2-{3-(aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl}ethylcarbamatehydrochloride

(1) A solution of3-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)-isoquinolinyl]propionicacid (0.78 g, 1.5 mmol), diphenylphosphoryl azide (0.39 ml, 1.8 mmol)and triethylamine (0.25 ml, 1.8 mmol) in N,N-dimethylformamide (10 ml)was stirred at room temperature for 2 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in toluene (20 ml) and themixture was refluxed with stirring. To the obtained mixture was addedmethanol (1 ml) and the mixture was refluxed with stirring for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasrecrystallized from tetrahydrofuran-diisopropyl ether to give methyl2-[4-butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)-isoquinolinyl]ethylcarbamate(0.30 g, 36.6%) as crystals.

Melting point 241–243° C. ¹H-NMR(CDCl₃) δ: 0.99 (3H, t, J=7.3 Hz),1.43–1.58 (2H, m), 1.72–1.91 (2H, m), 3.51 (2H, q, J=6.6 Hz), 3.61 (3H,s), 3.91 (2H, t, J=6.8 Hz), 4.45 (2H, t, J=6.6 Hz), 5.07 (2H, s), 5.47(1H, bs), 7.71–7.88 (5H, m), 8.47 (1H, s).

(2) Methyl2-{4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl}ethylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 185.5–186° C. Elemental analysis for C₂₃H₃₁N₃O₆Cl₂Calculated: C, 53.49; H, 6.05; N, 8.14. Found: C, 53.64; H, 6.11; N,8.30. ¹H-NMR(CDCl₃) δ: 1.04 (3H, t, J=7.3 Hz), 1.46 (9H, s), 1.52–1.67(2H, m), 1.80–1.94 (2H, m), 3.54 (2H, t, J=6.2 Hz), 3.59 (3H, s), 3.85(2H, t, J=6.5 Hz), 4.29 (2H, t, J=6.2 Hz), 4.52 (2H, d, J=5.8 Hz), 5.34(1H, s), 5.51 (1H, bs), 7.78 (1H, s), 8.46 (1H, s).

(3) Methyl3-{2-{3-(aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl}ethylcarbamatehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 230–231° C. Elemental analysis for C₁₈H₂₄N₃O₄Cl₃Calculated: C, 47.75; H, 5.34; N, 9.28. Found: C, 47.47; H, 5.47; N,9.10. ¹H-NMR(DMSO-d₆) δ: 0.99 (3H, t, J=7.3 Hz), 1.45–1.63 (2H, m),1.76–1.91 (2H, m), 3.29 (2H, q, J=6.4 Hz), 3.47 (3H, s), 3.91 (2H, t,J=6.4 Hz), 4.12 (2H, t, J=6.4 Hz), 4.23 (2H, d, J=4.4 Hz), 7.44 (1H,bs), 7.93 (1H, s), 8.39 (1H, s), 8.72 (3H, bs).

Example 55N-{2-{3-(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl}ethyl}-1-pyrrolidinecarboxamidehydrochloride

(1)N-{2-{4-Butoxy-6,7-dichloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-oxo-2(1H)-isoquinolinyl}ethyl}-1-pyrrolidinecarboxamide(synthesized according to the method similar to that in Example 4 (6))

Melting point 197–198° C. Elemental analysis for C₂₉H₃₀N₄O₅Cl₂ ½H₂OCalculated: C, 58.59; H, 5.26; N, 9.42. Found: C, 58.59; H, 5.54; N,9.32. ¹H-NMR(CDCl₃) δ: 0.98 (3H, t, J=7.3 Hz), 1.38–1.57 (2H, m),1.76–1.89 (6H, m), 3.23–3.30 (4H, m), 3.56 (2H, q, J=6.6 Hz), 3.89 (2H,t, J=6.8 Hz), 4.53 (2H, t, J=6.6 Hz), 5.08 (1H, bs), 5.12 (2H, s),7.70–7.85 (5H, m), 8.47 (1H, s).

(2)Tert-butyl{4-butoxy-6,7-dichloro-1-oxo-2-{2-(1-pyrrolidinylcarbonyl)amino}ethyl}-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example (6))

Melting point 161–162° C. Elemental analysis for C₂₆H₃₆N₄O₅Cl₂Calculated: C, 56.22; H, 6.53; N, 10.09. Found: C, 56.61; H, 6.24; N,9.99. ¹H-NMR(CDCl₃) δ: 1.03 (3H, t, J=7.3 Hz), 1.45 (9H, s), 1.52–1.66(2H, m), 1.80–1.91 (8H, m), 3.17–3.24 (4H, m), 3.61 (2H, q, J=6.3 Hz),3.88 (2H, t, J=6.6 Hz), 4.32 (2H, t, J=6.3 Hz), 4.53 (2H, d, J=6.0 Hz),5.09 (1H, bs), 6.07 (1H, bs), 7.81 (1H, s), 8.44 (1H, s).

(3)N-{2-{3-(Aminomethyl)-4-butoxy-6,7-dichloro-1-oxo-2(1H)-isoquinolinyl}ethyl}-1-pyrrolidinecarboxylicacid hydrochloride (synthesized according to the method similar to thatin Example 1 (7))

Melting point 190–192° C. Elemental analysis for C₂₁H₂₉N₄O₃Cl₃ 3/2H₂OCalculated: C, 48.61; H, 6.17; N, 10.80. Found: C, 48.85; H, 6.06; N,10.81. ¹H-NMR(DMSO-d₆) δ: 0.99 (3H, t, J=7.3 Hz), 1.48–1.63 (2H, m),1.79–1.91 (6H, m), 3.16–3.28 (6H, m), 3.92 (2H, t, J=6.4 Hz), 4.09 (2H,t, J=6.8 Hz), 4.31 (2H, bs), 6.80 (1H, bs), 7.92 (1H, s), 8.38 (1H, s),8.95 (3H, bs).

Example 563-(Aminomethyl)-4-butoxy-2-neopentylbenzo{g}isoquinolin-1(2H)-onehydrochloride

(1) Ethyl4-hydroxy-2-neopentyl-1-oxo-1,2-dihydrobenzo-{g}isoquinoline-3-carboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 140–141.5° C. Elemental analysis for C₂₁H₂₃NO₄ Calculated:C, 71.37; H, 6.56; N, 3.96. Found: C, 71.08; H, 6.36; N, 3.72.¹H-NMR(CDCl₃) δ: 0.87 (9H, s), 1.48 (3H, t, J=7.2 Hz), 4.50 (2H, q,J=7.2 Hz), 4.55 (2H, bs), 7.59–7.69 (2H, m), 8.05–8.12 (2H, m), 8.67(1H, s), 9.03 (1H, s) 11.11 (1H, s).

(2) Ethyl4-butoxy-2-neopentyl-1-oxo-1,2-dihydrobenzo{g}isoquinoline-3-carboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.96 (9H, s), 1.05 (3H, t, J=7.3 Hz), 1.48 (3H, t,J=7.1 Hz), 1.55–1.66 (2H, m), 1.74–1.95 (2H, m), 4.06 (2H, t, J=6.4 Hz),4.11 (2H, bs), 4.46 (2H, q, J=7.1 Hz), 7.52–7.67 (2H, m), 7.98–8.09 (2H,m), 8.24 (1H, s), 9.05 (1H, s).

(3)4-Butoxy-2-neopentyl-1-oxo-1,2-dihydrobenzo{g}isoquinoline-3-carboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 203–205° C. Elemental analysis for C₂₃H₂₇NO₄ Calculated:C, 72.42; H, 7.13; N, 3.67. Found: C, 72.39; H, 7.05; N, 3.53.¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.03 (3H, t, J=7.1 Hz), 1.48–1.66 (2H,m), 1.79–1.93 (2H, m), 4.06 (2H, t, J=6.6 Hz), 4.28 (2H, bs), 7.55–7.67(2H, m), 7.74–7.82 (2H, m), 8.03–8.08 (1H, m), 8.89 (1H, s).

(4) 4-Butoxy-3-hydroxymethyl-2-neopentyl-benzo{g}isoquinolin-1(2H)-one(synthesized according to the method similar to that in Example 4 (4))

Melting point 147–148° C. Elemental analysis for C₂₃H₂₉NO₃ Calculated:C, 75.17; H, 7.95; N, 3.81. Found: C, 75.12; H, 8.10; N, 3.65.¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.08 (3H, t, J=7.3 Hz), 1.56–1.75 (2H,m), 1.86–1.99 (2H, m), 2.73 (1H, bs), 3.97 (2H, t, J=6.6 Hz), 4.25 (2H,bs), 4.92 (2H, bs), 7.45–7.57 (2H, m), 7.76–7.80 (1H, m), 7.91 (1H, s),7.94–7.99 (1H, m), 8.85 (1H, s).

(5) 4-Butoxy-3-chloromethyl-2-neopentyl-benzo{g}isoquinolin-1(2H)-one(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.08 (3H, t, J=7.2 Hz), 1.57–1.76 (2H,m), 1.89–2.02 (2H, m), 4.05 (2H, t, J=6.5 Hz), 4.21 (2H, bs), 4.95 (2H,bs), 7.50–7.66 (2H, m), 7.98–8.09 (2H, m), 8.20 (1H, s), 9.04 (1H, s).

(6)2-{(4-Butoxy-2-neopentyl-1-oxo-1,2-dihydrobenzo{g}-isoqulinolin-3-yl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 244–245° C. Elemental analysis for C₃₁H₃₂N₂O₄ Calculated:C, 74.98; H, 6.50; N, 5.64. Found: C, 74.73; H, 6.58; N, 5.60.¹H-NMR(CDCl₃) δ: 1.02 (9H, s), 1.05 (3H, t, J=7.2 Hz), 1.53–1.71 (2H,m), 1.90–2.04 (2H, m), 4.12 (2H, bs), 4.15 (2H, t, J=6.8 Hz), 5.14 (2H,s), 7.48–7.64 (2H, m), 7.68–7.83 (4H, m), 7.96–8.06 (2H, m), 8.21 (1H,s), 9.01 (1H, s)

(7)Tert-butyl(4-butoxy-2-neopentyl-1-oxo-1,2-dihydrobenzo{g}isoquinolin-3-yl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

¹H-NMR(CDCl₃) δ: 1.01 (9H, s), 1.07 (3H, t, J=7.3 Hz), 1.47 (9H, s),1.50–1.73 (2H, m), 1.87–2.01 (2H, m), 3.96 (2H, t, J=6.4 Hz), 4.14 (2H,bs), 4.62 (2H, d, J=5.2 Hz), 4.73 (1H, bs), 7.48–7.64 (2H, m), 7.94–8.06(2H, m), 8.11 (1H, s), 9.00 (1H, s).

(8) 3-(Aminomethyl)-4-butoxy-2-neopentylbenzo{g}isoquinolin-1(2H)-onehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 231–232° C. Elemental analysis for C₂₃H₃₁N₂O₂ClCalculated: C, 68.55; H, 7.55; N, 6.95. Found: C, 68.30; H, 7.80; N,7.02. ¹H-NMR(DMSO-d₆) δ: 0.93 (9H, s), 1.04 (3H, t, J=7.1 Hz), 1.56–1.67(2H, m), 1.90–1.97 (2H, m), 4.05 (2H, bs), 4.14 (2H, bs), 4.30 (2H, bs),7.64–7.75 (2H, m), 8.19–8.27 (2H, m), 8.32 (1H, s), 8.63 (3H, bs), 8.99(1H, s).

Example 573-(Aminomethyl)-4-butoxy-6-methoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)-Tert-butyl4-hydroxy-2-neopentyl-6-fluoro-1-oxo-1,2-dihydro-3-isoquinoline-3-carboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 130–131° C. Elemental analysis for C₁₉H₂₄NO₄F Calculated:C, 65.31; H, 6.92; N, 4.01. Found: C, 65.32; H, 7.19; N, 3.92.¹H-NMR(CDCl₃) δ: 0.86 (9H, s), 1.65 (9H, s), 4.51 (2H, bs), 7.30–7.40(1H, m), 7.74 (1H, dd, J=2.6, 9.0 Hz), 8.46 (1H, dd, J=5.4, 9.0 Hz),10.68 (1H, s).

(2) Tert-butyl4-butoxy-2-neopentyl-6-fluoro-1-oxo-1,2-dihydro-3-isoquinoline-3-carboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.97 (9H, s), 1.01 (3H, t, J=6.8 Hz), 1.49–1.60 (2H,m), 1.63 (9H, s), 1.73–1.86 (2H, m), 3.96 (2H, t, J=6.6 Hz), 4.00 (2H,bs), 7.18–7.27 (1H, m), 7.35 (1H, dd, J=2.4, 9.4 Hz), 8.43 (1H, dd,J=5.4, 8.8 Hz).

(3) A solution of tert-butyl4-butoxy-2-neopentyl-6fluoro-1-oxo-1,2-dihydro-3-isoquinoline-3-carboxylate(6.08 g, 15 mmol) in trifluoroacetic acid (20 ml) was stirred at roomtemperature for 2 h. The reaction mixture was concentrated under reducedpressure, and the residue was recrystallized from ethyl acetate-n-hexaneto give4-butoxy-2-neopentyl-6-fluoro-1-oxo-1,2-dihydro-3-isoquinoline-3-carboxylicacid (4.98 g, 95.0%) as crystals.

Melting point 141–142° C. Elemental analysis for C₁₉H₂₄NO₄F Calculated:C, 65.31; H, 6.92; N, 4.01. Found: C, 65.38; H, 6.86; N, 3.90.¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 0.99 (3H, t, J=7.2 Hz), 1.48–1.60 (2H,m), 1.76–1.87 (2H, m), 4.02 (2H, t, J=6.5 Hz), 4.23 (2H, bs), 7.23–7.38(2H, m), 8.43 (1H, dd, J=5.5, 9.1 Hz).

(4) A solution (8.68 g, 45 mmol) of4-butoxy-2-neopentyl-6-fluoro-1-oxo-1,2-dihydro-3-isoquinoline-3carboxylicacid (1.05 g, 3 mmol) and 20% sodium methoxide in methanol was refluxedunder heating for 6 h. The reaction mixture was poured into water, and,after making the mixture acidic with 1N hydrochloric acid, extractedwith ethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was recrystallized from tetrahydrofuran-diethyl ether to give4-butoxy-6-methoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinoline-3-carboxylicacid (0.96 g, 88.9%) as crystals.

Melting point 194–196° C. Elemental analysis for C₂₀H₂₇NO₅ Calculated:C, 66.46; H, 7.53; N, 3.88. Found: C, 66.39; H, 7.45; N, 3.88.¹H-NMR(CDCl₃) δ: 0.91 (9H, s), 1.01 (3H, t, J=7.2 Hz), 1.51–1.62 (2H,m), 1.76–1.87 (2H, m), 3.91 (3H, s), 4.01 (2H, t, J=6.4 Hz), 4.13 (2H,bs), 6.91 (1H, d, J=2.4 Hz), 7.08 (1H, dd, J=2.4, 8.8 Hz), 8.17 (1H, d,J=8.8 Hz).

(5) 4-Butoxy-3-hydroxymethyl-6-methoxy-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 124–125° C. Elemental analysis for C₂₀H₂₉NO₄ Calculated:C, 69.14; H, 8.41; N, 4.03. Found: C, 69.06; H, 8.41; N, 3.96.¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.04 (3H, t, J=7.3 Hz), 1.56–1.67 (2H,m), 1.79–1.93 (2H, m), 3.01 (1H, bs), 3.89 (2H, t, J=6.2 Hz), 3.90 (3H,s), 4.17 (2H, bs), 4.85 (2H, bs), 6.94–6.98 (2H, m), 8.15–8.21 (1H, m).

(6) 4-Butoxy-3-chloromethyl-6-methoxy-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.04 (3H, t, J=7.4 Hz), 1.53–1.71 (2H,m), 1.82–1.95 (2H, m), 3.93 (3H, s), 3.96 (2H, t, J=6.2 Hz), 4.24 (2H,bs), 4.88 (2H, bs), 7.07–7.30 (2H, m), 8.33–8.38 (1H, m).

(7)2-{(4-Butoxy-6-methoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 145–146° C. Elemental analysis for C₂₈H₃₂N₂O₅ Calculated:C, 70.57; H, 6.77; N, 5.88. Found: C, 70.60; H, 6.83; N, 5.93.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.01 (3H, t, J=7.3 Hz), 1.51–1.66 (2H,m), 1.82–1.96 (2H, m), 3.92 (3H, s), 4.03 (2H, t, J=6.7 Hz), 4.24 (2H,bs), 5.07 (2H, bs), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.11 (1H, d, J=2.4Hz), 7.63–7.83 (4H, m), 8.32 (1H, d, J=8.8 Hz).

(8)Tert-butyl(4-butoxy-6-methoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 138.5–139° C. Elemental analysis for C₂₅H₃₈N₂O₅Calculated: C, 67.24; H, 8.58; N, 6.27. Found: C, 67.31; H, 8.85; N,6.43. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.4 Hz), 1.45 (9H,s), 1.51–1.64 (2H, m), 1.79–1.93 (2H, m), 3.87 (2H, t, J=6.4 Hz), 3.93(3H, s), 4.11 (2H, bs), 4.56 (2H, t, J=5.0 Hz), 4.68 (1H, bs), 7.03–7.09(2H, m), 8.33 (1H, d, J=9.6 Hz).

(9)3-(Aminomethyl)-4-butoxy-6-methoxy-2-neopentyl-1(2H)-1-oxo-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 172–174° C. Elemental analysis for C₂₀H₃₁N₂O₃Cl ¼H₂OCalculated: C, 62.00; H, 8.20; N, 7.23. Found: C, 61.90; H, 8.11; N,7.35. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.1 Hz), 1.52–1.64(2H, m), 1.77–1.92 (2H, m) 3.93 (3H, s), 3.94 (2H, t, J=6.4 Hz), 4.08(2H, bs), 4.23 (2H, bs), 7.09 (1H, d, J=2.4 Hz), 7.20 (1H, dd, J=2.4,8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 8.59 (3H, bs).

Example 583-(Aminomethyl)-6-benzyloxy-4-butoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)6-Benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinoline-3-carboxylicacid (synthesized according to the method similar to that in Example 57(4))

Melting point 163–164° C. Elemental analysis for C₂₆H₃₁NO₅ Calculated:C, 71.37; H, 7.14; N, 3.20. Found: C, 71.13; H, 7.10; N, 2.94.¹H-NMR(CDCl₃) δ: 0.89 (9H, s), 0.99 (3H, t, J=7.1 Hz), 1.41–1.59 (2H,m), 1.69–1.84 (2H, m), 3.91 (2H, t, J=6.4 Hz), 4.13 (2H, bs), 5.17 (2H,s), 7.01 (1H, d, J=2.4 Hz), 7.18 (1H, dd, J=2.4, 9.0 Hz), 7.33–7.44 (5H,m), 8.22 (1H, d, J=9.0 Hz).

(2)6-Benzyloxy-4-butoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 95–95.5° C. Elemental analysis for C₂₆H₃₃NO₄ Calculated:C, 73.73; H, 7.85; N, 3.31. Found: C, 73.44; H, 7.77; N, 3.38.¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 1.02 (3H, t, J=7.4 Hz), 1.45–1.64 (2H,m), 1.73–1.86 (2H, m) 2.57 (1H, bs), 3.80 (2H, t, J=6.4 Hz), 4.18 (2H,bs), 4.84 (2H, bs), 5.18 (2H, s), 7.06–7.11 (2H, m), 7.31–7.47 (5H, m),8.23 (1H, d, J=8.0 Hz).

(3) 6-Benzyloxy-4-butoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.97 (9H, s), 1.03 (3H, t, J=7.1 Hz), 1.46–1.65 (2H,m), 1.74–1.88 (2H, m), 3.84 (2H, t, J=6.4 Hz), 4.14 (2H, bs), 4.86 (2H,bs), 5.21 (2H, s), 7.12–7.48 (7H, m), 8.36 (1H, d, J=9.2 Hz).

(4)2-{(6-Benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Elemental analysis for C₃₄H₃₆N₂O₅ ½H₂O Calculated: C, 72.71; H, 6.64; N,4.99. Found: C, 72.74; H, 6.42; N, 5.26. ¹H-NMR(CDCl₃) δ: 0.99 (3H, t,J=7.3 Hz), 1.00 (9H, s), 1.39–1.58 (2H, m), 1.64–1.89 (2H, m), 3.92 (2H,t, J=6.7 Hz), 4.10 (2H, bs), 5.06 (2H, bs), 5.20 (2H, s), 7.11–7.17 (2H,m), 7.31–7.47 (5H, m), 7.70–7.90 (4H, m), 8.30–8.35 (1H, m).

(5)Tert-butyl(6-benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 114–115° C. Elemental analysis for C₃₁H₄₂N₂O₅ Calculated:C, 71.42; H, 8.10; N, 5.36. Found: C, 71.34; H, 8.40; N, 5.39.¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.02 (3H, t, J=7.4 Hz), 1.45 (9H, s),1.46–1.59 (2H, m), 1.73–1.87 (2H, m), 3.76 (2H, t, J=6.4 Hz), 4.11 (2H,bs), 4.54 (2H, d, J=5.2 Hz), 4.66 (1H, bs), 5.21 (2H, s), 7.08 (1H, d,J=2.6 Hz), 7.14 (1H, dd, J=2.6, 8.8 Hz), 7.32–7.48 (5H, m), 8.33 (1H, d,J=8.8 Hz).

(6)3-(Aminomethyl)-6-benzyloxy-4-butoxy-2-neopentyl-1(2H)-1-oxo-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 234–236° C. Elemental analysis for C₂₆H₃₅N₂O₃ClCalculated: C, 68.03; H, 7.69; N, 6.10. Found: C, 67.96; H, 7.64; N,5.93. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H, s), 0.98 (3H, t, J=7.5 Hz), 1.45–1.56(2H, m), 1.71–1.82 (2H, m), 3.84 (2H, t, J=6.2 Hz), 4.07 (2H, bs), 4.21(2H, bs), 5.33 (2H, bs), 7.11 (1H, d, J=2.2 Hz), 7.27 (1H, dd, J=2.2,8.8 Hz), 7.34–7.50 (5H, m), 8.19 (1H, d, J=8.8 Hz), 8.52 (3H, bs).

Example 593-(Aminomethyl)-4-butoxy-6-hydroxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) A suspension oftert-butyl(6-benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(2.61 g, 5 mmol) and 5% palladium carbon (1.5 g) in tetrahydrofuran (10ml) and ethanol (10 ml) was stirred under a hydrogen atmosphere at roomtemperature for 2 h. After filtering off 5% palladium carbon, thefiltrate was concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-n-hexane to givetert-butyl(4-butoxy-6-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-methylcarbamate(4.98 g, 95.0%) as crystals.

Melting point 195.5–197° C. Elemental analysis for C₂₄H₃₆N₂O₅Calculated: C, 66.64; H, 8.39; N, 6.48. Found: C, 66.57; H, 8.58; N,6.49. ¹H-NMR(CDCl₃) δ: 0.96 (3H, t, J=7.4 Hz), 0.99 (9H, s), 1.45 (9H,s), 1.46–1.55 (2H, m), 1.72–1.81 (2H, m), 3.82 (2H, t, J=6.6 Hz), 4.11(2H, bs), 4.56 (2H, d, J=5.2 Hz), 4.78 (1H, bs), 7.06–7.11 (2H, m), 8.26(1H, d, J=9.2 Hz), 8.79 (1H, bs).

(2)3-(Aminomethyl)-4-butoxy-6-hydroxy-2-neopentyl-1(2H)-1-oxo-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 264–266° C. Elemental analysis for C₁₉H₂₉N₂O₃Cl ¼H₂OCalculated: C, 61.11; H, 7.96; N, 7.50. Found: C, 61.22; H, 7.77; N,7.56. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H, s), 1.00 (3H, t, J=7.1 Hz), 1.50–1.61(2H, m), 1.77–1.92 (2H, m), 3.89 (2H, t, J=6.2 Hz), 4.05 (2H, bs), 4.20(2H, bs), 7.03–7.08 (2H, m), 8.11 (1H, d, J=8.2 Hz), 8.50 (1H, s), 10.67(1H, bs).

Example 603-(Aminomethyl)-4-butoxy-2-neopentyl-6-propoxy-1(2H)-isoquinolinonehydrochloride

(1) A solution oftert-butyl(4-butoxy-6-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.52 g, 1.2 mmol), 1-bromopropane (0.16 ml, 1.2 mmol) and potassiumcarbonate (0.16 g, 1.2 mmol) in N,N-dimethylformamide (10 ml) wasstirred at room temperature for 12 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to givetert-butyl(4-butoxy-2-neopentyl-1-oxo-6-propoxy-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.50 g, 89.3%) as an amorphous.

Elemental analysis for C₂₇H₄₂N₂O₅ ¼H₂O Calculated: C, 67.68; H, 8.94; N,5.85. Found: C, 67.87; H, 8.89; N, 5.95. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s),1.04 (3H, t, J=7.2 Hz), 1.08 (3H, t, J=7.4 Hz), 1.45 (9H, s), 1.50–1.65(2H, m), 1.79–1.93 (4H, m), 3.83 (2H, t, J=6.6 Hz) 4.01 (2H, bs), 4.04(2H, t, J=6.4 Hz), 4.55 (2H, d, J=5.2 Hz), 4.67 (1H, bs), 7.02–7.08 (2H,m), 8.31 (1H, d, J=9.6 Hz).

(2)3-(Aminomethyl)-4-butoxy-2-neopentyl-6-propoxy-1(2H)-1-oxo-isoquinolinehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 202–204° C. Elemental analysis for C₂₂H₃₅N₂O₃ClCalculated: C, 64.29; H, 8.58; N, 6.82. Found: C, 64.05; H, 8.29; N,6.64. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.4 Hz), 1.02 (3H,t, J=7.3 Hz), 1.53–1.63 (2H, m), 1.72–1.86 (4H, m), 3.94 (2H, t, J=6.2Hz), 4.07 (2H, bs), 4.10 (2H, t, J=6.5 Hz), 4.23 (2H, bs), 7.07 (1H, d,J=2.5 Hz), 7.19 (1H, dd, J=2.5, 8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.51(3H, bs).

Example 61 3-(Aminomethyl)-4,6-dibutoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl(4,6-dibutoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl))methylcarbamate(synthesized according to the method similar to that in Example 60 (1))

Elemental analysis for C₂₈H₄₄N₂O₅ Calculated: C, 68.82; H, 9.08; N,5.73. Found: C, 68.66; H, 8.87; N, 5.54. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s),1.00 (3H, t, J=7.4 Hz), 1.04 (3H, t, J=7.0 Hz), 1.45 (9H, s), 1.51–1.64(4H, m), 1.77–1.90 (4H, m), 3.86 (2H, t, J=6.4 Hz), 4.08 (2H, t, J=6.5Hz), 4.14 (2H, bs), 4.56 (2H, d, J=5.2 Hz), 4.67 (1H, bs), 7.02–7.08(2H, m), 8.32 (1H, d, J=9.4 Hz).

(2) 3-(Aminomethyl)-4,6-dibutoxy-2-neopentyl-1(2H)-1-oxo-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 184–186° C. Elemental analysis for C₂₃H₃₇N₂O₃Cl ¾H₂OCalculated: C, 63.00; H, 8.85; N, 6.39. Found: C, 62.85; H, 8.88; N,6.14. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 0.96 (3H, t, J=7.8 Hz), 1.00 (3H,t, J=7.4 Hz), 1.42–1.60 (4H, m), 1.63–1.92 (4H, m), 3.94 (2H, t, J=6.2Hz), 4.11 (2H, bs), 4.15 (2H, t, J=6.5 Hz), 4.23 (2H, bs), 7.07 (1H, d,J=2.4 Hz), 7.18 (1H, dd, J=2.4, 8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.57(3H, bs).

Example 623-(Aminomethyl)-4-butoxy-6-(2-methoxyethoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl{4-butoxy-6-(2-methoxyethoxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 60 (1))

Elemental analysis for C₂₇H₄₂N₂O₆ Calculated: C, 66.10; H, 8.63; N,5.71. Found: C, 66.22; H, 8.59; N, 5.41. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s),1.03 (3H, t, J=7.4 Hz), 1.45 (9H, s), 1.52–1.64 (2H, m), 1.78–1.89 (2H,m), 3.49 (3H, s), 3.80–3.88 (4H, m), 4.20 (2H, bs), 4.22–4.25 (2H, m),4.55 (2H, d, J=5.4 Hz), 4.66 (1H, bs), 7.08–7.13 (2H, m), 8.30–8.35 (1H,m).

(2)3-(Aminomethyl)-4-butoxy-6-(2-methoxyethoxy)-2-neopentyl-1(2H)-1-oxo-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 188–189° C. Elemental analysis for C₂₂H₃₅N₂O₄ClCalculated: C, 61.89; H, 8.26; N, 6.56. Found: C, 61.55; H, 8.34; N,6.59. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.51–1.62(2H, m), 1.77–1.88 (2H, m), 3.33 (3H, s), 3.71–3.75 (2H, m), 3.94 (2H,t, J=6.4 Hz), 4.07 (2H, bs), 4.25–4.30 (4H, m), 7.09 (1H, d, J=2.4 Hz),7.21 (1H, dd, J=2.4, 8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.55 (3H, bs).

Example 633-(Aminomethyl)-7-benzyloxy-4-butoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) A solution of 5-benzyloxy-2-(ethoxycarbonyl)benzoic acid (21.86 g,120 mmol), ethyl 2-(neopentylamino)acetate (20.79 g, 120 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.76 g,150 mmol) and 1-hydroxybenzotriazole (22.97 g, 150 mmol) inN,N-dimethylformamide (200 ml) was stirred at room temperature for 3 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in N,N-dimethylformamide (300 ml), and potassium carbonate(33.17 g, 240 mmol) and benzyl bromide (35.7 ml, 300 mmol) were added.The mixture was stirred at room temperature for 12 h. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was dissolved inethanol (50 ml) and 20% sodium ethoxide ethanol solution (34.04 g, 100mmol) was added. The mixture was stirred at room temperature for 1 h.The reaction mixture was poured into 1N hydrochloric acid (150 ml) andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyand the component eluted earlier was concentrated to give ethyl7-benzyloxy-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylateas an oil. To a solution of the obtained ethyl7-benzyloxy-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(3.26 g, 8 mmol), 1-butanol (1.1 ml, 12 mmol) and tributylphosphine (4.0ml, 16 mmol) in tetrahydrofuran (30 ml) was added1,1′-(azodicarbonyl)dipiperidine (4.04 g, 16 mmol) and the mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography to give ethyl7-benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(3.61 g, 97.0%) as an oil.

¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.00 (3H, t, J=7.4 Hz), 1.43 (3H, t,J=7.2 Hz), 1.51–1.66 (2H, m), 1.73–1.87 (2H, m), 3.94 (2H, t, J=6.5 Hz),4.14 (2H, bs), 4.42 (2H, q, J=7.2 Hz), 5.20 (2H, bs), 7.34–7.50 (6H, m),7.73 (1H, d, J=8.8 Hz), 7.96 (1H, d, J=2.6 Hz).

(2)7-Benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinoline-3-carboxylicacid (synthesized according to the method similar to that in Example 57(4))

Elemental analysis for C₂₆H₃₁NO₅ Calculated: C, 71.37; H, 7.14; N, 3.20.Found: C, 71.11; H, 7.35; N, 3.08. ¹H-NMR(CDCl₃) δ: 0.91 (9H, s), 0.95(3H, t, J=7.4 Hz), 1.44–1.59 (2H, m), 1.74–1.89 (2H, m), 4.00 (2H, t,J=6.6 Hz), 4.35 (2H, bs), 5.20 (2H, s), 7.31–7.51 (6H, m), 7.60 (1H, d,J=8.8 Hz), 7.84 (1H, d, J=2.6 Hz).

(3)7-Benzyloxy-4-butoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 156.5–157° C. Elemental analysis for C₂₆H₃₃NO₄ Calculated:C, 73.73; H, 7.85; N, 3.31. Found: C, 73.76; H, 7.62; N, 3.42.¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.00 (3H, t, J=7.4 Hz), 1.47–1.64 (2H,m), 1.76–1.90 (2H, m), 2.57 (1H, bs), 3.87 (2H, t, J=6.4 Hz), 4.23 (2H,bs), 4.86 (2H, bs), 5.17 (2H, s), 7.25–7.51 (6H, m), 7.59 (1H, d, J=8.8Hz), 7.82 (1H, d, J=2.2 Hz).

(4) 7-Benzyloxy-4-butoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.03 (3H, t, J=7.4 Hz), 1.54–1.69 (2H,m), 1.80–1.94 (2H, m), 3.94 (2H, t, J=6.4 Hz), 4.17 (2H, bs), 4.90 (2H,bs), 5.20 (2H, s), 7.33–7.50 (6H, m), 7.69 (1H, d, J=8.8 Hz), 7.96 (1H,d, J=2.4 Hz).

(5)2-{(7-Benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole1,3(2H)-dione (synthesized according to the method similar to that inExample 4 (6))

Melting point 120–121° C. Elemental analysis for C₃₄H₃₆N₂O₅ Calculated:C, 73.89; H, 6.57; N, 5.07. Found: C, 73.77; H, 6.28; N, 5.29.¹H-NMR(CDCl₃) δ: 1.00 (3H, t, J=7.2 Hz), 1.02 (9H, s), 1.44–1.62 (2H,m), 1.81–1.95 (2H, m), 4.02 (2H, t, J=6.8 Hz), 4.06 (2H, bs), 5.08 (2H,bs), 5.18 (2H, s), 7.30–7.50 (6H, m), 7.67–7.90 (5H, m), 7.93 (1H, d,J=2.6 Hz).

(6)Tert-butyl(7-benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 122–123° C. Elemental analysis for C₃₁H₄₂N₂O₅ Calculated:C, 71.42; H, 8.10; N, 5.36. Found: C, 71.31; H, 8.19; N, 5.39.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.02 (3H, t, J=7.2 Hz), 1.45 (9H, s),1.46–1.64 (2H, m), 1.78–1.92 (2H, m), 3.86 (2H, t, J=6.6 Hz), 4.17 (2H,bs), 4.56 (2H, t, J=5.2 Hz), 4.65 (1H, bs), 5.19 (2H, s), 7.30–7.50 (6H,m), 7.64 (1H, d, J=8.6 Hz), 7.93 (1H, d, J=2.6 Hz).

(7)3-(Aminomethyl)-7-benzyloxy-4-butoxy-2-neopentyl-1(2H)-1-oxo-isoquinolinehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 202–204° C. Elemental analysis for C₂₆H₃₅N₂O₃Cl H₂OCalculated: C, 65.46; H, 7.82; N, 5.87. Found: C, 65.57; H, 7.47; N,5.49. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 0.99 (3H, t, J=7.3 Hz), 1.48–1.60(2H, m), 1.76–1.91 (2H, m), 3.92 (2H, t, J=6.4 Hz), 4.08 (2H, bs), 4.23(2 H, bs), 5.27 (2H, s), 7.31–7.55 (6H, m), 7.74 (1H, d, J=8.6 Hz), 7.80(1H, d, J=2.6 Hz), 8.51 (3H, bs).

Example 643-(Aminomethyl)-4-butoxy-7-hydroxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl(4-butoxy-7-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 59 (1))

Melting point 237–238° C. Elemental analysis for C₂₄H₃₆N₂O₅ Calculated:C, 66.64; H, 8.39; N, 6.48. Found: C, 66.54; H, 8.41; N, 6.36.¹H-NMR(CDCl₃) δ: 0.88 (9H, s), 0.96 (3H, t, J=7.2 Hz), 1.40 (2H, m),1.44–1.59 (9H, s), 1.40–1.55 (2H, m), 1.69–1.79 (2H, m), 3.80 (2H, t,J=6.2 Hz), 3.94 (2H, bs), 4.39 (2H, d, J=4.8 Hz), 7.21 (1H, bs), 7.24(1H, dd, J=2.4, 8.4 Hz), 7.56 (1H, d, J=2.4 Hz), 7.58 (1H, d, J=8.4 Hz),10.15 (1H, s).

(2)3-(Aminomethyl)-4-butoxy-7-hydroxy-2-neopentyl-1(2H)-1-oxo-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 238–239° C. Elemental analysis for C₁₉H₂₉N₂O₃ClCalculated: C, 61.86; H, 7.92; N, 7.59. Found: C, 61.80; H, 7.84; N,7.52. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H, s), 0.98 (3H, t, J=7.3 Hz), 1.44–1.63(2H, m), 1.75–1.89 (2H, m), 3.91 (2H, t, J=6.5 Hz), 4.08 (2H, bs), 4.20(2H, bs), 7.31 (1H, dd, J=2.8, 8.6 Hz), 7.62 (1H, d, J=2.8 Hz), 7.64(1H, d, J=8.6 Hz), 8.43 (3H, bs), 10.33 (1H, s).

Example 653-(Aminomethyl)-4-butoxy-7-methoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl(4-butoxy-7-methoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 60 (1))

Melting point 171–172° C. Elemental analysis for C₂₅H₃₈N₂O₅ ¼H₂OCalculated: C, 66.57; H, 8.60; N, 6.21. Found: C, 66.65; H, 8.77; N,6.15. ¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.02 (3H, t, J=7.4 Hz), 1.45 (9H,s), 1.51–1.66 (2H, m), 1.78–1.92 (2H, m), 3.86 (2H, t, J=6.4 Hz), 3.93(3H, s), 4.14 (2H, bs), 4.56 (2H, d, J=4.8 Hz), 4.66 (1H, bs), 7.28 (1H,dd, J=2.6, 8.8 Hz), 7.63 (1H, d, J=8.8 Hz), 7.82 (1H, d, J=2.6 Hz).

(2)3-(Aminomethyl)-4-butoxy-7-methoxy-2-neopentyl-1(2H)-1-oxo-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 210–212° C. Elemental analysis for C₂₀H₃₁N₂O₃ClCalculated: C, 62.00; H, 8.20; N, 7.23. Found: C, 61.97; H, 8.07; N,7.28. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 0.99 (3H, t, J=7.3 Hz), 1.45–1.64(2H, m), 1.77–1.91 (2H, m), 3.90 (3H, s), 3.92 (2H, t, J=6.2 Hz), 4.10(2H, bs), 4.23 (2H, bs), 7.45 (1H, dd, J=2.6, 8.8 Hz), 7.70 (1H, d,J=2.6 Hz), 7.73 (1H, d, J=8.8 Hz), 8.52 (3H, bs).

Example 663-(Aminomethyl)-4-butoxy-7-ethoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl(4-butoxy-7-ethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 60 (1))

Melting point 140–142° C. Elemental analysis for C₂₆H₄₀N₂O₅ Calculated:C, 67.80; H, 8.75; N, 6.08. Found: C, 67.57; H, 8.51; N, 6.10.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.02 (3H, t, J=7.4 Hz), 1.44 (9H, s),1.45 (3H, t, J=7.0 Hz), 1.49–1.67 (2H, m), 1.78–1.92 (2H, m), 3.85 (2H,t, J=6.6 Hz), 4.11 (2H, bs), 4.16 (2H, q, J=7.0 Hz), 4.56 (2H, d, J=5.2Hz), 4.65 (1H, bs), 7.27 (1H, dd, J=2.4, 8.8 Hz), 7.62 (1H, d, J=8.8Hz), 7.80 (1H, d, J=2.4 Hz).

(2)3-(Aminomethyl)-4-butoxy-7-ethoxy-2-neopentyl-1(2H)-1-oxo-isoquinolinehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₂₁H₃₃N₂O₃Cl ½H₂O Calculated: C, 62.13; H, 8.44;N, 6.90. Found: C, 62.21; H, 8.40; N, 7.15. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H,s), 0.99 (3H, t, J=7.3 Hz), 1.38 (3H, t, J=6.8 Hz), 1.49–1.60 (2H, m),1.69–1.92 (2H, m), 3.92 (2H, bs), 4.12–4.22 (6H, m), 7.44 (1H, dd,J=2.6, 8.8 Hz), 7.62–7.75 (2H, m), 8.54 (3H, bs).

Example 673-(Aminomethyl)-4-butoxy-2-neopentyl-7-propoxy-1(2H)-isoquinolinonehydrochloride.

(1)Tert-butyl(4-butoxy-2-neopentyl-1-oxo-7-propoxy-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 60 (1))

Melting point 143.5–144.5° C. Elemental analysis for C₂₇H₄₂N₂O₅Calculated: C, 68.32; H, 8.92; N, 5.90. Found: C, 68.30; H, 8.95; N,6.02. ¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.02 (3H, t, J=7.4 Hz), 1.06 (3H,t, J=7.4 Hz), 1.45 (9H, s), 1.51–1.65 (2H, m), 1.76–1.92 (4H, m), 3.85(2H, t, J=6.6 Hz), 4.06 (2H, t, J=6.8 Hz), 4.09 (2H, bs), 4.56 (2H, d,J=4.4 Hz), 4.62 (1H, bs), 7.28 (1H, dd, J=2.7, 8.8 Hz), 7.62 (1H, d,J=8.8 Hz), 7.80 (1H, d, J=2.7 Hz).

(2)3-(Aminomethyl)-4-butoxy-2-neopentyl-7-propoxy-1(2H)-1-oxo-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 216–218° C. Elemental analysis for C₂₂H₃₅N₂O₃Cl ¼H₂OCalculated: C, 63.60; H, 8.61; N, 6.74. Found: C, 63.84; H, 8.67; N,6.80. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 0.99 (3H, t, J=7.4 Hz), 1.01 (3H,t, J=7.3 Hz), 1.49–1.70 (2H, m), 1.73–1.90 (4H, m), 3.92 (2H, t, J=6.6Hz), 4.07 (2H, t, J=6.4 Hz), 4.10 (2H, bs), 4.23 (2H, bs), 7.45 (1H, dd,J=2.8, 8.8 Hz), 7.68 (1H, d, J=2.8 Hz), 7.72 (1H, d, J=8.8 Hz), 8.51(3H, bs).

Example 68 3-(Aminomethyl)-4,7-dibutoxy-2-neopentyl-1(2H)-isoquinolinehydrochloride

(1)Tert-butyl(4-butoxy-7-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 60 (1))

Elemental analysis for C₂₈H₄₄N₂O₅ Calculated: C, 68.82; H, 9.08; N, 5.73Found: C, 68.79; H, 9.34; N, 5.72. ¹-NMR(CDCl₃) δ: 0.99 (3H, t, J=7.2Hz), 1.00 (9H, s), 1.02 (3H, t, J=7.2 Hz), 1.45 (9H, s), 1.46–1.64 (4H,m), 1.74–1.89 (4H, m), 3.85 (2H, t, J=6.4 Hz), 4.07 (2H, bs), 4.10 (2H,t, J=6.4 Hz), 4.55 (2H, d, J=4.4 Hz), 4.61 (1H, bs), 7.28 (1H, dd,J=2.8, 8.8 Hz), 7.62 (1H, d, J=8.8 Hz), 7.80 (1H, d, J=2.8 Hz).

(2) 3-(Aminomethyl)-4,7-dibutoxy-2-neopentyl-1(2H)-1-oxo-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 192.5–193° C. Elemental analysis for C₂₃H₃₇N₂O₃Cl ¼H₂OCalculated: C, 64.32; H, 8.80; N, 6.52. Found: C, 64.38; H, 8.83; N,6.49. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 0.95–1.02 (6H, m), 1.41–1.60 (4H,m), 1.68–1.87 (4H, m), 3.92 (2H, t, J=6.1 Hz), 4.11 (2H, t, J=6.2 Hz),4.14 (2H, bs), 4.23 (2H, bs), 7.44 (1H, dd, J=2.6, 8.8 Hz), 7.68 (1H, d,J=2.6 Hz), 7.72 (1H, d, J=8.8 Hz), 8.54 (3H, bs).

Example 693-(Aminomethyl)-4-butoxy-5,6-dimethoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) A solution of ethyl 6-formyl-2,3-dimethoxybenzoate (5.24 g, 22mmol), sodium dihydrogen phosphate (3.60 g, 30 mmol) and2-methyl-2-butene (10.3 ml, 96.8 mmol) in t-butanol (20 ml),tetrahydrofuran (20 ml) and water (20 ml) was stirred at roomtemperature for 10 min. To the obtained mixture was added sodiumchlorite (6.76 g, 74.8 mmol) and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-n-hexane togive 2-(ethoxycarbonyl)-3,4-dimethoxybenzoic acid (4.51 g, 80.7%) ascrystals.

Melting point 148–149° C. Elemental analysis for C₁₂H₁₄O₆ Calculated: C,56.69; H, 5.55. Found: C, 56.52; H, 5.64. ¹H-NMR(CDCl₃) δ: 1.38 (3H, t,J=7.2 Hz), 3.87 (3H, s), 3.95 (3H, s), 4.43 (2H, q, J=7.2 Hz), 6.97 (1H,d, J=8.8 Hz), 7.88 (1H, d, J=8.8 Hz).

(2) A solution of 2-(ethoxycarbonyl)-3,4-dimethoxybenzoic acid (4.45 g,17.5 mmol), ethyl 2-(neopentylamino)acetate (3.47 g, 20 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.83 g, 20mmol) in N,N-dimethylformamide (50 ml) was stirred at room temperaturefor 3 h. The reactions mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in ethanol (50 ml) and 20% sodium ethoxide ethanolsolution (34.04 g, 100 mmol) was added thereto. The mixture was stirredat room temperature for 1 h. The reaction mixture was poured into 1Nhydrochloric acid (150 ml) and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give ethyl5,6-dimethoxy-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(3.21 g, 50.6%) as an oil.

Elemental analysis for C₁₉H₂₅NO₆ ½H₂O Calculated: C, 61.28; H, 7.04; N,3.76. Found: C, 61.61; H, 6.67; N, 3.85. ¹H-NMR(CDCl₃) δ: 0.90 (9H, s),1.43 (3H, t, J=7.2 Hz), 4.01 (3H, s), 4.04 (3H, s), 4.21 (2H, bs), 4.44(2H, q, J=7.2 Hz), 7.24 (1H, d, J=9.2 Hz), 8.28. (1H, d, J=9.2 Hz), 9.56(1H, s).

(3) Ethyl4-butoxy-5,6-dimethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

Melting point 70–71° C. Elemental analysis for C₂₃H₃₃NO₆ Calculated: C,65.85; H, 7.93; N, 3.34. Found: C, 65.64; H, 7.79; N, 3.45.¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 0.96 (3H, t, J=7.2 Hz), 1.34–1.52 (5H,m), 1.65–1.80 (2H, m), 3.63 (3H, s), 3.89–3.96 (4H, m), 4.00 (3H, s),4.42 (2H, q, J=7.2 Hz), 7.19 (1H, d, J=8.8 Hz), 8.28 (1H, d, J=8.8 Hz).

(4)4-Butoxy-5,6-dimethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 144–145.5° C. Elemental analysis for C₂₁H₂₉NO₆ ¼H₂OCalculated: C, 63.70; H, 7.51; N, 3.54. Found: C, 63.81; H, 7.28; N,3.60. ¹H-NMR(CDCl₃) δ: 0.91 (9H, s), 0.95 (3H, t, J=7.2 Hz), 1.37–1.52(2H, m), 1.72–1.86 (2H, m), 3.87 (3H, s), 3.89–3.97 (2H, m), 4.00 (3H,s), 4.10 (2H, bs), 7.22 (1H, d, J=8.9 Hz), 8.27 (1H, d, J=8.9 Hz).

(5)4-Butoxy-5,6-dimethoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 140–141° C. Elemental analysis for C₂₁H₃₁NO₅ ¼H₂OCalculated: C, 66.03; H, 8.31; N, 3.67. Found: C, 66.13; H, 8.22; N,3.77. ¹H-NMR(CDCl₃) δ: 0.97 (9H, s), 1.00 (3H, t, J=7.2 Hz), 1.46–1.64(2H, m), 1.75–1.80 (2H, m), 2.39 (1H, s), 3.84 (3H, s), 3.86 (2H, t,J=7.0 Hz), 3.98 (3H, s), 4.17 (2H, bs), 4.86 (2H, bs), 7.11 (1H, d,J=9.0 Hz), 8.20 (1H, d, J=9.0 Hz).

(6)4-Butoxy-3-chloromethyl-5,6-dimethoxy-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.02 (3H, t, J=7.4 Hz), 1.47–1.64 (2H,m), 1.76–1.87 (2H, m), 3.85 (3H, s), 3.89 (2H, t, J=6.2 Hz), 3.99 (3H,s), 4.12 (2H, bs), 4.92 (2H, bs), 7.24 (1H, d, J=8.8 Hz), 8.28 (1H, d,J=8.8 Hz).

(7)2-{(4-Butoxy-5,6-dimethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 122–123° C. Elemental analysis for C₂₉H₃₄N₂O₆ Calculated:C, 68.76; H, 6.76; N, 5.53. Found: C, 68.72; H, 6.71; N, 5.58.¹H-NMR(CDCl₃) δ: 0.95 (3H, t, J=7.4 Hz), 0.99 (9H, s), 1.41–1.53 (2H,m), 1.75–1.89 (2H, m), 3.86 (3H, s), 3.94–3.95 (4H, m), 3.99 (3H, s),5.13 (2H, bs), 7.15 (1H, d, J=9.0 Hz), 7.67–7.84 (4H, m), 8.25 (1H, d,J=9.0 Hz).

(8)Tert-butyl(4-butoxy-5,6-dimethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Elemental analysis for C₂₆H₄₀N₂O₆ Calculated: C, 65.52; H, 8.46; N,5.88. Found: C, 65.17; H, 8.30; N, 5.89. ¹H-NMR(CDCl₃) δ: 0.98 (9H, s),0.99 (3H, t, J=7.3 Hz), 1.45 (9H, s), 1.46–1.55 (2H, m), 1.74–1.84 (2H,m), 3.80 (2H, t, J=6.2 Hz), 3.85 (3H, s), 3.99 (3H, s), 4.14 (2H, bs),4.56 (2H, d, J=5.6 Hz), 4.67 (1H, bs), 7.15 (1H, d, J=9.0 Hz), 8.26 (1H,d, J=9.0 Hz).

(9)3-(Aminomethyl)-4-butoxy-5,6-dimethoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 7))

Melting point 156–157° C. Elemental analysis for C₂₁H₃₃N₂O₄ClCalculated: C, 61.08; H, 8.05; N, 6.78. Found: C, 60.71; H, 8.05; N,6.78. ¹H-NMR(DMSO-d₆) δ: 0.88 (9H, s), 0.97 (3H, t, J=7.3 Hz), 1.43–1.54(2H, m), 1.76–1.83 (2H, m), 3.76 (3H, s), 3.79 (2H, bs), 3.94 (3H, s),4.07 (2H, bs), 4.22 (2H, s), 7.40 (1H, d, J=9.0 Hz), 8.11 (1H, d, J=9.0Hz), 8.52 (3H, bs).

Example 703-(Aminomethyl)-4-butoxy-6,7-dimethoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) 2-(Ethoxycarbonyl)-4,5-dimethoxybenzoic acid (synthesized accordingto the method similar to that in Example 69 (1))

Melting point 130–131° C. Elemental analysis for C₁₂H₁₄O₆ ¼H₂OCalculated: C, 55.70; H, 5.65. Found: C, 56.06; H, 5.53. ¹H-NMR(CDCl₃)δ: 1.39 (3H, t, J=7.2 Hz), 3.98 (6H, s), 4.40 (2H, q, J=7.2 Hz), 7.22(1H, s), 7.50 (1H, s), 8.01 (1H, s).

(2) Ethyl6,7-dimethoxy-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 69 (2))

Elemental analysis for C₁₉H₂₅NO₆ Calculated: C, 62.80; H, 6.93; N, 3.85.Found: C, 62.58; H, 6.89; N, 3.82. ¹H-NMR(CDCl₃) δ: 0.85 (9H, s), 1.47(3H, t, J=7.2 Hz), 4.04 (6H, s), 4.47 (2H, q, J=7.2 Hz), 4.55 (2H, bs),7.49 (1H, s), 7.85 (1H, s), 11.04 (1H, s).

(3) Ethyl4-butoxy-6,7-dimethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 1.02 (3H, t, J=7.3 Hz), 1.44 (3H, t,J=7.3 Hz), 1.49–1.67 (2H, m), 1.74–1.87 (2H, m), 3.96 (2H, t, J=6.4 Hz),4.01 (3H, s), 4.02 (3H, s), 4.14 (2H, bs), 4.42 (2H, q, J=7.1 Hz), 7.15(1H, s), 7.83 (1H, s).

(4)4-Butoxy-6,7-dimethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 209–210° C. Elemental analysis for C₂₁H₂₉NO₆ Calculated:C, 64.43; H, 7.47; N, 3.58. Found: C, 64.14; H, 7.34; N, 3.46.¹H-NMR(CDCl₃) δ: 0.91 (9H, s), 1.01 (3H, t, J=7.2 Hz), 1.44–1.65 (2H,m), 1.74–1.88 (2H, m), 3.92 (3H, s), 4.03–4.18 (7H, m), 6.60 (1H, s),7.31 (1H, s).

(5)4-Butoxy-6,7-dimethoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 142–143° C. Elemental analysis for C₂₁H₃₁NO₅ ¼H₂OCalculated: C, 66.03; H, 8.31; N, 3.67. Found: C, 66.32; H, 8.46; N,3.83. ¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 1.03 (3H, t, J=7.3 Hz), 1.55–1.67(2H, m), 1.77–1.87 (2H, m), 3.65 (1H, bs), 3.80 (2H, t, J=6.2 Hz), 3.95(3H, s), 4.02 (3H, s), 4.22 (2H, bs), 4.84 (2H, bs), 6.76 (1H, s), 7.57(1H, s).

(6)4-Butoxy-3-chloromethyl-6,7-dimethoxy-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.05 (3H, t, J=7.3 Hz), 1.58–1.73 (2H,m), 1.82–1.93 (2H, m), 3.97 (2H, t, J=6.4 Hz), 4.02 (6H, s), 4.21 (2H,bs), 4.90 (2H, bs), 7.12 (1H, s), 7.82 (1H, s).

(7)2-{(4-Butoxy-6,7-dimethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 210–212° C. Elemental analysis for C₂₉H₃₄N₂O₆ Calculated:C, 68.76; H, 6.76; N, 5.53. Found: C, 68.61; H, 6.65; N, 5.55.¹H-NMR(CDCl₃) δ: 1.01 (3H, t, J=7.4 Hz), 1.02 (9H, s), 1.49–1.67 (2H,m), 1.82–1.96 (2H, m), 3.99 (3H, s), 4.00 (3H, s), 4.03 (2H, t, J=6.6Hz), 4.10 (2H, bs), 5.07 (2H, s), 7.13 (1H, s), 7.68–7.83 (5H, m).

(8)Tert-butyl(4-butoxy-6,7-dimethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 197–198° C. Elemental analysis for C₂₆H₄₀N₂O₆ ½H₂OCalculated: C, 64.31; H, 8.51; N, 5.77. Found: C, 64.68; H, 8.43; N,5.62. ¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.04 (3H, t, J=7.2 Hz), 1.46 (9H,s), 1.55–1.70 (2H, m), 1.79–1.93 (2H, m), 3.86 (2H, t, J=6.4 Hz), 4.00(3H, s), 4.05 (3H, s), 4.10 (2H, bs), 4.56 (2H, d, J=5.4 Hz), 4.80 (1H,bs), 7.03 (1H, s), 7.77 (1H, s).

(9)3-(Aminomethyl)-4-butoxy-6,7-dimethoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 231–233° C. Elemental analysis for C₂₁H₃₃N₂O₄Cl H₂OCalculated: C, 58.53; H, 8.19; N, 6.50. Found: C, 58.77; H, 8.23; N,6.61. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.53–1.65(2H, m), 1.77–1.88 (2H, m), 3.90 (3H, s), 3.94 (3H, s), 3.95 (2H, t,J=7.8 Hz), 4.09 (2H, bs), 4.22 (2H, s), 7.10 (1H, s), 7.65 (1H, s), 8.56(3H, bs).

Example 715-(Aminomethyl)-4-butoxy-6-neopentylthieno[2,3-c]pyridin-7(6H)-onehydrochloride

(1) 3-(Ethoxycarbonyl)-2-thiophenecarboxylic acid (synthesized accordingto the method similar to that in Example 69 (1))

Melting point 80–81° C. Elemental analysis for C₈H₈O₄S Calculated: C,47.99; H, 4.03. Found: C, 47.91; H, 3.79. ¹H-NMR(CDCl₃) δ: 1.46 (3H, t,J=7.1 Hz), 4.50 (2H, q, J=7.1 Hz), 7.57 (1H, d, J=5.3 Hz), 7.63 (1H, d,J=5.3 Hz).

(2) Ethyl4-hydroxy-6-neopentyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridin-5-carboxylate(synthesized according to the method similar to that in Example 69 (2))

Melting point 95.5–97° C. Elemental analysis for C₁₅H₁₉NO₄S Calculated:C, 58.23; H, 6.19; N, 4.53. Found: C, 58.12; H, 6.01; N, 4.48.¹H-NMR(CDCl₃) δ: 0.85 (9H, s), 1.46 (3H, t, J=7.2 Hz), 4.47 (2H, q,J=7.2 Hz), 4.53 (2H, bs), 7.55 (1H, d, J=5.1 Hz), 7.72 (1H, d, J=5.1Hz), 10.66 (1H, s).

(3) Ethyl4-butoxy-6-neopentyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-5-carboxylate(synthesized according to the method similar to that in Example 1 (2))

Melting point 74–74.5° C. Elemental analysis for C₁₉H₂₇NO₄S Calculated:C, 62.44; H, 7.45; N, 3.83. Found: C, 62.48; H, 7.70; N, 3.89.¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 0.99 (3H, t, J=7.3 Hz), 1.43 (3H, t,J=7.2 Hz), 1.49–1.60 (2H, m), 1.70–1.84 (2H, m), 4.00 (2H, t, J=6.6 Hz),4.14 (2H, bs), 4.41 (2H, q, J=7.2 Hz), 7.32 (1H, d, J=5.2 Hz), 7.72 (1H,d, J=5.2 Hz).

(4)4-Butoxy-6-neopentyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-5-carboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 111–112° C. Elemental analysis for C₁₇H₂₃NO₄S Calculated:C, 60.51; H, 6.87; N, 4.15. Found: C, 60.53; H, 6.87; N, 4.29.¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 0.98 (3H, t, J=7.4 Hz), 1.43–1.61 (2H,m), 1.74–1.84 (2H, m), 4.08 (2H, t, J=6.4 Hz), 4.31 (2H, bs), 5.98 (1H,bs), 7.34 (1H, d, J=5.2 Hz), 7.75 (1H, d, J=5.2 Hz).

(5) 4-Butoxy-5-hydroxymethyl-6-neopentylthieno[2,3-c]pyridin-7(6H)-one(synthesized according to the method similar to that in Example 4 (4))

Melting point 110–111° C. Elemental analysis for C₁₇H₂₅NO₃S Calculated:C, 63.13; H, 7.79; N, 4.33. Found: C, 63.11; H, 7.59; N, 4.44.¹H-NMR(CDCl₃) δ: 0.97 (9H, s), 1.02 (3H, t, J=7.4 Hz), 1.47–1.68 (2H,m), 1.76–1.89 (2H, m), 3.98 (2H, t, J=6.6 Hz), 4.22 (2H, bs), 4.86 (2H,bs), 7.24 (1H, d, J=5.4 Hz), 7.62 (1H, d, J=5.4 Hz).

(6) 4-Butoxy-5-chloromethyl-6-neopentylthieno[2,3-c]pyridin-7(6H)-one(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.01 (9H, s), 1.02 (3H, t, J=7.3 Hz), 1.52–1.63 (2H,m), 1.78–1.88 (2H, m), 4.01 (2H, t, J=6.4 Hz), 4.20 (2H, bs), 4.89 (2H,bs), 7.30 (1H, d, J=5.2 Hz), 7.69 (1H, d, J=5.2 Hz).

(7)2-{(4-Butoxy-6-neopentyl-7-oxo-6,7-dihydrothieno{2,3-c}pyridin-5-yl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 118–119° C. Elemental analysis for C₂₅H₂₈N₂O₄S Calculated:C, 66.35; H, 6.24; N, 6.19. Found: C, 66.26; H, 6.17; N, 6.27.¹H-NMR(CDCl₃) δ: 0.99 (3H, t, J=7.2 Hz), 1.03 (9H, s), 1.41–1.60 (2H,m), 1.76–1.91 (2H, m), 4.08 (2H, t, J=6.8 Hz), 4.14 (2H, bs), 5.08 (2H,s), 7.30 (1H, d, J=5.0 Hz), 7.67 (1H, d, J=5.0 Hz), 7.69–7.84 (4H, m).

(8)Tert-butyl(4-butoxy-6-neopentyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridin-5-yl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 131–131.5° C. Elemental analysis for C₂₂H₃₄N₂O₄SCalculated: C, 62.53; H, 8.11; N, 6.63. Found: C, 62.47; H, 8.13; N,6.63. ¹H-NMR(CDCl₃) δ: 1.01 (9H, s), 1.02 (3H, t, J=7.1 Hz), 1.44 (9H,s), 1.46–1.68 (2H, m), 1.75–1.89 (2H, m), 3.93 (2H, t, J=6.4 Hz), 4.17(2H, bs), 4.56 (2H, d, J=5.2 Hz), 4.70 (1H, bs), 7.27 (1H, d, J=5.5 Hz),7.68 (1H, d, J=5.5 Hz).

(9) 5-(Aminomethyl)-4-butoxy-6-neopentylthieno[2,3-c]pyridin-7(6H)-onehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₁₇H₂₇N₂O₂ClS ¼H₂O Calculated: C, 56.18; H, 7.63;N, 7.71. Found: C, 56.01; H, 7.64; N, 7.67. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H,s), 0.97 (3H, t, J=7.4 Hz), 1.45–1.56 (2H, m), 1.73–1.83 (2H, m), 4.01(2H, t, J=6.2 Hz), 4.13 (2H, bs), 4.23 (2H, bs), 7.47 (1H, d, J=5.1 Hz),8.16 (1H, d, J=5.1 Hz), 8.53 (3H, bs).

Example 726-(Aminomethyl)-7-butoxy-5-neopentylthieno[3,2-c]pyridin-4(5H)-onehydrochloride

(1) 2-(Ethoxycarbonyl)-3-thiophenecarboxylic acid (synthesized accordingto the method similar to that in Example 69 (1))

Melting point 94–95° C. Elemental analysis for C₈H₈O₄S Calculated: C,47.99; H, 4.03. Found: C, 47.91; H, 3.79. ¹H-NMR(CDCl₃) δ: 1.28 (3H, t,J=7.0 Hz), 4.28 (2H, q, J=7.0 Hz), 7.32 (1H, d, J=5.1 Hz), 7.89 (1H, d,J=5.1 Hz).

(2) Ethyl7-hydroxy-5-neopentyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-6-carboxylate(synthesized according to the method similar to that in Example 69 (2))

Melting point 110–111° C. Elemental analysis for C₁₅H₁₉NO₄S Calculated:C, 58.23; H, 6.19; N, 4.53. Found: C, 58.28; H, 6.19; N, 4.50.¹H-NMR(CDCl₃) δ: 0.86 (9H, s), 1.47 (3H, t, J=7.2 Hz), 4.48 (2H, q,J=7.2 Hz), 7.58 (1H, d, J=5.2 Hz), 7.72 (1H, d, J=5.2 Hz), 10.62 (1H,s).

(3) Ethyl7-butoxy-5-neopentyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-6-carboxylate(synthesized according to the method similar to that in Example 1 (2))

¹H-NMR(CDCl₃) δ: 0.94 (9H, s), 0.99 (3H, t, J=7.5 Hz), 1.43 (3H, t,J=7.2 Hz), 1.43–1.61 (2H, m), 1.70–1.84 (2H, m), 4.07 (2H, t, J=6.6 Hz),4.14 (2H, bs), 4.41 (2H, q, J=7.2 Hz), 7.41 (1H, d, J=5.3 Hz), 7.68 (1H,d, J=5.3 Hz).

(4)7-Butoxy-5-neopentyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-6-carboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 137–138° C. Elemental analysis for C₁₇H₂₃NO₄S Calculated:C, 60.51; H, 6.87; N, 4.15. Found: C, 60.66; H, 6.86; N, 4.10.¹H-NMR(CDCl₃) δ: 0.93 (9H, s), 0.98 (3H, t, J=7.4 Hz), 1.43–1.61 (2H,m), 1.72–1.86 (2H, m), 4.14 (2H, t, J=6.4 Hz), 4.21 (2H, bs), 6.83 (1H,bs), 7.44 (1H, d, J=5.3 Hz), 7.68 (1H, d, J=5.3 Hz).

(5) 7-Butoxy-6-hydroxymethyl-5-neopentylthieno[3,2-c]pyridin-4(5H)-one(synthesized according to the method similar to that in Example 4 (4))

Melting point 102–103° C. Elemental analysis for C₁₇H₂₅NO₃S ½H₂OCalculated: C, 61.42; H, 7.88; N, 4.21. Found: C, 61.39; H, 7.61; N,4.36. ¹H-NMR(CDCl₃) δ: 0.95 (9H, s), 1.02 (3H, t, J=7.2 Hz), 1.47–1.66(2H, m), 1.75–1.89 (2H, m), 3.10 (1H, bs), 4.04 (2H, t, J=6.5 Hz), 4.15(2H, bs), 4.83 (2H, bs), 7.22–7.26 (1H, m), 7.52–7.56 (1H, m).

(6) 7-Butoxy-6-chloromethyl-5-neopentylthieno[3,2-c]pyridin-4(5H)-one(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 1.01 (9H, s), 1.02 (3H, t, J=7.3 Hz), 1.52–1.63 (2H,m), 1.77–1.88 (2H, m), 4.08 (2H, t, J=6.4 Hz), 4.14 (2H, bs), 4.87 (2H,bs), 7.35 (1H, d, J=5.5 Hz), 7.68 (1H, d, J=5.5 Hz).

(7)2-{(7-Butoxy-5-neopentyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-6-yl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 136–137° C. Elemental analysis for C₂₅H₂₈N₂O₄S Calculated:C, 66.35; H, 6.24; N, 6.19. Found: C, 66.27; H, 6.14; N, 6.22.¹H-NMR(CDCl₃) δ: 0.99 (3H, t, J=7.2 Hz), 1.02 (9H, s), 1.45–1.60 (2H,m), 1.76–1.90 (2H, m), 4.14 (2H, bs), 4.16 (2H, t, J=6.6 Hz), 5.07 (2H,s), 7.29 (1H, d, J=5.2 Hz), 7.64 (1H, d, J=5.2 Hz), 7.69–7.83 (4H, m).

(8)Tert-butyl(7-butoxy-5-neopentyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-6-yl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 141–142° C. Elemental analysis for C₂₂H₃₄N₂O₄S Calculated:C, 62.53; H, 8.11; N, 6.63. Found: C, 62.50; H, 8.08; N, 6.66.¹H-NMR(CDCl₃) δ: 1.01 (9H, s), 1.02 (3H, t, J=7.1 Hz), 1.44 (9H, s),1.49–1.64 (2H, m), 1.74–1.88 (2H, m), 4.00 (2H, t, J=6.4 Hz), 4.14 (2H,bs), 4.56 (2H, d, J=5.0 Hz), 4.70 (1H, bs), 7.29 (1H, d, J=5.1 Hz), 7.64(1H, d, J=5.1 Hz).

(9) 6-(Aminomethyl)-7-butoxy-5-neopentylthieno[3,2-c]pyridin-4(5H)-onehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 204–206° C. Elemental analysis for C₁₇H₂₇N₂O₂ClSCalculated: C, 56.89; H, 7.58; N, 7.80. Found: C, 56.98; H, 7.46; N,7.61. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 0.98 (3H, t, J=7.4 Hz), 1.44–1.59(2H, m), 1.71–1.92 (2H, m), 4.07 (2H, t, J=6.4 Hz), 4.09 (2H, bs), 4.24(2H, d, J=5.3 Hz), 7.56 (1H, d, J=5.3 Hz), 7.77 (1H, d, J=5.3 Hz), 8.58(3H, bs).

Example 743-(Aminomethyl)-6-bromo-4-butoxy-2-isobutyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-bromo-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 74–75° C. Elemental analysis for C₁₆H₁₈NO₄Br Calculated:C, 52.19; H, 4.93; N, 3.80. Found: C, 52.15; H, 4.89; N, 3.85.¹H-NMR(CDCl₃) δ: 0.82 (6H, d, J=6.6 Hz), 1.46 (3H, t, J=7.2 Hz),1.78–1.88 (1H, m), 4.39 (2H, d, J=5.6 Hz), 4.49 (2H, q, J=7.2 Hz), 7.78(1H, dd, J=2.0, 8.4 Hz), 8.30 (1H, d, J=2.0 Hz), 8.31 (1H, d, J=8.4 Hz),11.14 (1H, s).

(2) Ethyl6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

Melting point 88–89° C. Elemental analysis for C₂₀H₂₆NO₄Br Calculated:C, 56.61; H, 6.18; N, 3.30. Found: C, 56.64; H, 6.13; N, 3.38.¹H-NMR(CDCl₃) δ: 0.90 (6H, d, J=7.0 Hz), 1.01 (3H, t, J=7.4 Hz), 1.44(3H, t, J=7.2 Hz), 1.48–1.63 (2H, m), 1.72–1.83 (2H, m), 2.05–2.19 (1H,m), 3.88 (2H, d, J=7.4 Hz), 3.95 (2H, t, J=6.4 Hz), 4.46 (2H, q, J=7.2Hz), 7.65 (1H, dd, J=2.0, 8.6 Hz), 7.88 (1H, d, J=2.0 Hz), 8.29 (1H, d,J=8.6 Hz).

(3)6-Bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 177–178° C. Elemental analysis for C₁₈H₂₂NO₄Br Calculated:C, 54.56; H, 5.60; N, 3.53. Found: C, 54.57; H, 5.63; N, 3.57.¹H-NMR(CDCl₃) δ: 0.90 (6H, d, J=6.6 Hz), 1.00 (3H, t, J=7.4 Hz),1.45–1.63 (2H, m), 1.75–1.89 (2H, m), 2.07–2.23 (1H, m), 4.01 (2H, t,J=6.4 Hz), 4.02 (2H, d, J=8.6 Hz), 6.81 (1H, bs), 7.65 (1H, dd, J=1.8,8.6 Hz), 7.81 (1H, d, J=1.8 Hz), 8.23 (1H, d, J=8.6 Hz).

(4) 6-Bromo-4-butoxy-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 92–93° C. Elemental analysis for C₁₈H₂₄NO₃Br ½H₂OCalculated: C, 55.25; H, 6.43; N, 3.58. Found: C, 55.62; H, 6.35; N,3.75. ¹H-NMR(CDCl₃) δ: 0.93 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.4 Hz),1.50–1.68 (2H, m), 1.79–1.93 (2H, m), 2.11–2.28 (1H, m), 2.47 (1H, bs),3.88 (2H, t, J=6.4 Hz), 4.08 (2H, d, J=7.8 Hz), 4.80 (2H, s), 7.55 (1H,d, J=8.6 Hz), 7.80 (1H, s), 8.18 (1H, d, J=8.6 Hz).

(5) 6-Bromo-4-butoxy-3-chloromethyl-2-isobutyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=7.0 Hz), 1.05 (3H, t, J=7.2 Hz),1.52–1.75 (2H, m), 1.86–1.96 (2H, m), 2.04–2.23 (1H, m), 3.98 (2H, t,J=6.4 Hz), 4.07 (2H, d, J=7.4 Hz), 4.80 (2H, s), 7.63 (1H, dd, J=2.0,8.4 Hz), 7.88 (1H, d, J=2.0 Hz), 8.29 (1H, d, J=8.4 Hz).

(6)2-{(6-Bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=7.0 Hz), 1.00 (3H, t, J=7.3 Hz),1.44–1.58 (2H, m), 1.79–1.95 (2H, m), 2.08–2.22 (1H, m), 3.95–4.05 (4H,m), 5.02 (2H, s), 7.59 (1H, dd, J=2.0, 8.8 Hz), 7.71–7.90 (5H, m), 8.27(1H, d, J=8.8 Hz).

(7)Tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 138–139° C. Elemental analysis for C₂₃H₃₃N₂O₄BrCalculated: C, 57.38; H, 6.91; N, 5.82. Found: C, 57.41; H, 6.79; N,5.76. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.3 Hz),1.46 (9H, s), 1.53–1.67 (2H, m), 1.80–1.93 (2H, m), 2.05–2.23 (1H, m),3.85 (2H, t, J=6.6 Hz), 3.98 (2H, d, J=7.6 Hz), 4.41 (2H, d, J=5.4 Hz),4.73 (1H, bs), 7.59 (1H, dd, J=2.0, 8.6 Hz), 7.82 (1H, d, J=2.0 Hz),8.26 (1H, d, J=8.6 Hz).

(8) 3-(Aminomethyl)-6-bromo-4-butoxy-2-isobutyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 133–134° C. Elemental analysis for C₁₈H₂₆N₂O₂BrCl ½H₂OCalculated: C, 50.66; H, 6.38; N, 6.56. Found: C, 51.05; H, 6.56; N,6.68. ¹H-NMR(DMSO-d₆) δ: 0.88 (6H, d, J=7.0 Hz), 1.00 (3H, t, J=7.4 Hz),1.46–1.65 (2H, m), 1.76–1.91 (2H, m), 1.96–2.10 (1H, m), 3.93 (2H, t,J=6.4 Hz), 3.96 (2H, d, J=7.6 Hz), 4.18 (2H, d, J=4.4 Hz), 7.79 (1H, dd,J=2.0, 8.6 Hz), 7.87 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=8.6 Hz), 8.69(3H, bs).

Example 75 Methyl3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride

(1) A mixture oftert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 74 (7))(2.41 g, 5 mmol), 1,3-bis(diphenylphosphino)propane (0.21 g, 0.5 mmol)and triethylamine (0.77 ml, 5.5 mmol) in dimethyl sulfoxide (30 ml) andmethanol (20 ml) was stirred under a carbon monoxide atmosphere at roomtemperature for 10 min. To the obtained mixture was added palladiumacetate (0.11 g, 0.5 mmol) and the mixture was stirred with heatingunder a carbon monoxide atmosphere at 60° C. for 12 h. The reactionmixture was poured into water and extracted with ethyl acetate. Afterwashing the extract with water, the extract was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give methyl4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(1.92 g, 83.5%) as crystals.

Melting point 148–149° C. Elemental analysis for C₂₅H₃₆N₂O₆ Calculated:C, 65.20; H, 7.88; N, 6.08. Found: C, 65.30; H, 7.67; N, 6.17.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.8 Hz), 1.05 (3H, t, J=7.3 Hz), 1.47(9H, S), 1.56–1.71 (2H, m), 1.83–1.93 (2H, m), 2.05–2.25 (1H, m), 3.89(2H, t, J=6.6 Hz), 3.99 (3H, s), 4.01 (2H, d, J=7.6 Hz), 4.53 (2H, d,J=5.4 Hz), 4.77 (1H, bs), 8.09 (1H, dd, J=1.9, 8.4 Hz), 8.40 (1H, d,J=1.9 Hz), 8.47 (1H, d, J=8.4 Hz).

(2) Methyl3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 135–136° C. Elemental analysis for C₂₀H₂₉N₂O₄ClCalculated: C, 60.52; H, 7.36; N, 7.06. Found: C, 60.20; H, 7.48; N,7.02. ¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.3 Hz),1.51–1.70 (2H, m), 1.80–1.92 (2H, m), 1.99–2.11 (1H, m), 3.95–4.01 (7H,m), 4.21 (2H, s), 8.11 (1H, dd, J=1.4, 8.2 Hz), 8.35 (1H, d, J=1.4 Hz),8.41 (1H, d, J=8.2 Hz), 8.70 (3H, bs).

Example 763-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid hydrochloride

(1) To a solution of methyl4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 75 (1))(1.61 g, 3.5 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) wasadded 1N sodium hydroxide (5 ml). The obtained mixture was stirred atroom temperature for 2 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-diethyl ether to give4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (1.54 g, 98.7%) as crystals.

Melting point 185–186° C. Elemental analysis for C₂₄H₃₄N₂O₆ Calculated:C, 64.55; H, 7.67; N, 6.27. Found: C, 64.77; H; 7.40; N, 6.10.¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.07 (3H, t, J=7.4 Hz), 1.49(9H, S), 1.50–1.72 (2H, m), 1.84–1.98 (2H, m), 2.14–2.21 (1H, m), 3.90(2H, t, J=6.4 Hz), 4.00 (2H, d, J=6.8 Hz), 4.55 (2H, d, J=5.01 Hz), 5.37(1H, bs), 8.08–8.13 (1H, m), 8.35–8.46 (2H, m).

(2)3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylichydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 238–239° C. Elemental analysis for C₁₉H₂₇N₂O₄ClCalculated: C, 59.60; H, 7.11; N, 7.32. Found: C, 59.42; H, 7.04; N,7.18. ¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.01 (3H, t, J=7.4 Hz),1.50–1.69 (2H, m), 1.80–1.93 (2H, m), 1.99–2.12 (1H, m), 3.97 (2H, t,J=6.4 Hz), 3.99 (2H,d, J=7.6 Hz), 4.21 (2H, s), 8.09 (1H, dd, J=1.4, 8.4Hz), 8.34 (1H, d, J=1.4 Hz), 8.38 (1H, d, J=8.4 Hz), 8.69 (3H, bs).

Example 773-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamidehydrochloride

(1) A solution of4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (Example 76 (1)) (0.45 g, 3.5 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2mmol) and 1-hydroxybenzotriazole ammonium salt (0.30 g, 2 mmol) inN,N-dimethylformamide (10 ml) was stirred at room temperature for 3 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas recrystallized from ethyl acetate-diisopropyl ether to givetert-butyl{(6-aminocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.35 g, 79.5%) as crystals.

Melting point 159–160° C. Elemental analysis for C₂₄H₃₅N₃O₅ Calculated:C, 64.70; H, 7.92; N, 9.43. Found: C, 64.53; H, 8.01; N, 9.53.¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=7.0 Hz), 1.03 (3H, t, J=7.3 Hz), 1.48(9H, S), 1.49–1.63 (2H, m), 1.80–1.95 (2H, m), 2.10–2.21 (1H, m), 3.87(2H, t, J=6.4 Hz), 4.00 (2H, d, J=7.2 Hz), 4.52 (2H, d, J=5.6 Hz), 5.07(1H, bs), 5.99 (1H, bs), 6.48 (1H, bs), 7.75 (1H, d, J=8.0 Hz), 8.10(1H, s), 8.35 (1H, d, J=8.0 Hz).

(2)3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 171–173° C. Elemental analysis for C₁₉H₂₈N₃O₃Cl H₂OCalculated: C, 57.06; H, 7.56; N, 10.51. Found: C, 57.41; H, 7.62; N,10.59. ¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=7.0 Hz), 1.01 (3H, t, J=7.3Hz), 1.48–1.66 (2H, m), 1.80–2.07 (3H, m), 3.94–4.00 (4H, m), 4.20 (2H,s), 7.70 (1H, s), 8.04 (1H, dd, J=1.6, 8.4 Hz) 8.22 (1H, d, J=1.6 Hz),8.33 (1H, d, J=8.4 Hz), 8.35 (1H, s), 8.60 (3H, bs).

Example 783-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarbonitrilehydrochloride

(1) A solution oftert-butyl{(6-aminocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(Example 77 (1)) (0.54 g, 1.2 mmol) and cyanuric chloride (0.66 g, 3.6mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas recrystallized from ethyl acetate-n-hexane to givetert-butyl(4-butoxy-6-cyano-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.41 g, 80.4%) as crystals.

Melting point 126–127° C. ¹H-NMR(CDCl₃) δ: 9.97 (6H, d, J=6.6 Hz), 1.05(3H, t, J=7.3 Hz), 1.47 (9H, s), 1.48–1.67 (2H, m), 1.82–1.96 (2H, m),2.11–2.25 (1H, m), 3.86 (2H, t, J=6.4 Hz), 4.02 (2H, d, J=7.0 Hz), 4.53(2H, d, J=5.2 Hz), 4.73 (1H, bs), 7.68 (1H, d, J=8.0 Hz), 8.01 (1H, s),8.50 (1H, d, J=8.0 Hz).

(2)3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarbonitrilehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 135–136° C. ¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz),1.00 (3H, t, J=7.2 Hz), 1.41–1.64 (2H, m), 1.81–1.91 (2H, m), 1.99–2.08(1H, m), 3.93–4.02 (4H, m), 4.20 (2H, s), 7.99 (1H, d, J=8.2 Hz), 8.24(1H, s), 8.42 (1H, d, J=8.2 Hz), 8.74 (3H, bs).

Example 793-(Aminomethyl)-4-butoxy-6-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinehydrochloride

(1) To a solution of4-butoxy-3-{{(tert-butoxycarbonyl)-amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 76(1)) (0.45 g, 3.5 mmol) and N-methylmorpholine (0.13 ml, 1.2 mmol) intetrahydrofuran (10 ml) was added ethyl chloroformate (0.12 ml, 1.2mmol) at 0° C., and the mixture was stirred at 0° C. for 10 min. To theobtained mixture was added sodium tetrahydroborate (0.11 g, 3 mmol) andthe mixture was stirred at 0° C. for 1 h. The reaction mixture waspoured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-diisopropyl ether to givetert-butyl(4-butoxy-6-hydroxymethyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.33 g, 76.7%) as crystals.

Melting point 153–154° C. Elemental analysis for C₂₄H₃₆N₂O₅ Calculated:C, 66.64; H, 8.39; N, 6.48. Found: C, 66.61; H, 8.21; N, 6.44.¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.01 (3H, t, J=7.4 Hz),1.40–1.57 (11H, m), 1.78–1.92 (2H, m), 2.11–2.24 (1H, m), 3.80 (2H, t,J=6.8 Hz), 3.97 (2H, d, J=7.8 Hz), 4.50 (2H, d, J=5.4 Hz), 4.82 (2H, s),5.25 (1H, bs), 7.39–7.51 (2H, m), 8.17–8.21 (1H, m).

(2)3-(Aminomethyl)-4-butoxy-6-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₁₉H₂₉N₂O₃Cl ½H₂O Calculated: C, 60.39; H, 8.00;N, 7.41. Found: C, 60.00; H, 7.07; N, 7.07. ¹H-NMR(DMSO-d₆) δ: 0.87 (6H,d, J=6.4 Hz), 1.00 (3H, t, J=7.1 Hz), 1.51–1.62 (2H, m), 1.82–2.02 (3H,m), 3.91–3.99 (4H, m), 4.69 (2H, d, J=5.2 Hz), 5.30 (2H, s), 5.53 (1H,bs), 7.52–7.62 (1H, m), 7.74 (1H, s), 8.21–8.30 (1H, m), 8.64 (3H, bs).

Example 80N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}-N′-methylureahydrochloride

(1) A solution of4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 76(1)) (0.45 g, 1 mmol), diphenylphosphoryl azide (0.26 ml, 1.2 mmol) andtriethylamine (0.17 ml, 1.2 mmol) in N,N-dimethylformamide (10 ml) wasstirred at room temperature for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in toluene (20 ml) and themixture was refluxed with stirring for 1 h. To the obtained mixture wasadded a solution of 2N methylamine in tetrahydrofuran (1 ml, 2 mmol),and the mixture was refluxed with stirring for 1 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was recrystallized fromtetrahydrofuran-diisopropyl ether to give tert-butyl{4-butoxy-2-isobutyl-6-{{(methylamino)carbony}-amino}-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.39 g, 83.0%) as an amorphous.

Elemental analysis for C₂₅H₃₈N₄O₅ Calculated: C, 63.27; H, 8.07; N,11.81. Found: C, 62.96; H, 8.35; N, 11.55. ¹H-NMR(CDCl₃) δ: 0.93 (6H, d,J=5.8 Hz), 0.95 (3H, t, J=6.6 Hz), 1.45–1.54 (11H, m), 1.64–1.82 (2H,m), 2.05–2.17 (1H, m), 2.86 (3H, d, J=4.4 Hz), 3.83 (2H, t, J=6.5 Hz),3.98 (2H, d, J=7.4 Hz), 4.50 (2H, d, J=5.2 Hz), 5.02 (1H, bs), 5.98 (1H,bs), 6.99–7.04 (2H, m), 8.06–8.10 (1H, m), 8.39 (1H, s).

(2)N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}-N′-methylureahydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 181–183° C. Elemental analysis for C₂₀H₃₁N₄O₃Cl ½H₂OCalculated: C, 57.20; H, 7.68; N, 13.34. Found: C, 57.13; H, 7.66; N,13.40. ¹H-NMR(DMSO-d₆) δ: 0.87 (6H, d, J=6.6 Hz), 0.99 (3H, t, J=7.1Hz), 1.46–1.65 (2H, m), 1.78–2.07 (3H, m), 3.87–3.93 (4H, m), 4.14 (2H,d, J=4.6 Hz), 6.74 (1H, bs), 7.48 (1H, dd, J=2.0, 8.8 Hz), 8.04 (1H, d,J=2.0 Hz), 8.10 (1H, d, J=8.8 Hz), 8.53 (3H, bs), 9.60 (1H, s).

Example 81 Methyl3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinylcarbamatehydrochloride

(1) Methyl4-butoxy-3-{{(tert-butoxycarbonyl)amino}-methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinylcarbamate(synthesized according to the method similar to that in Example 80 (1))

Elemental analysis for C₂₅H₃₈N₄O₅ Calculated: C, 63.14; H, 7.84; N,8.84. Found: C, 62.99; H, 7.87; N, 9.01. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d,J=7.0 Hz), 1.03 (3H, t, J=7.1 Hz), 1.46 (9H, s), 1.52–1.67 (2H, m),1.81–1.95 (2H, m), 2.09–2.23 (1H, m), 3.82 (3H, s), 3.88 (2H, t, J=6.6Hz), 3.98 (2H, d, J=7.4 Hz), 4.51 (2H, d, J=5.4 Hz), 4.80 (1H, bs), 7.09(1H, bs), 7.36 (1H, dd, J=2.0, 8.8 Hz), 7.89 (1H, d, J=2.0 Hz), 8.33(1H, d, J=8.8 Hz).

(2) Methyl3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinylcarbamatehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 166–168° C. Elemental analysis for C₂₀H₃₀N₃O₄Cl ¼H₂OCalculated: C, 57.69; H, 7.38; N, 10.09. Found: C, 57.59; H, 7.66; N,10.02. ¹H-NMR(DMSO-d₆) δ: 0.87 (6H, d, J=6.6 Hz), 1.00 (3H, t, J=7.4Hz), 1.47–1.65 (2H, m), 1.79–2.04 (3H, m), 3.73 (3H, s), 3.89–3.94 (4H,m), 4.15 (2H, d, J=4.6 Hz), 7.63 (1H, dd, J=1.8, 8.8 Hz), 8.03 (1H, d,J=1.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.62 (3H, bs), 10.28 (1H, s).

Example 826-Amino-3-(aminomethyl)-4-butoxy-2-isobutyl-1(2H)-isoquinolinonedihydrochloride

(1) A solution of4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 76(1)) (0.45 g, 1 mmol), diphenylphosphoryl azide (0.26 ml, 1.2 mmol) andtriethylamine (0.17 ml, 1.2 mmol) in N,N-dimethylformamide, (10 ml) wasstirred at room temperature for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in toluene (20 ml) and themixture was refluxed with stirring for 1 h. To the obtained mixture wasadded 9H-fluorenylmethanol (0.29 g, 1.5 mmol) and the mixture wasrefluxed with stirring for 1 h. The reaction mixture was poured intowater and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography and recrystallized from tetrahydrofuran-diisopropyl etherto give 9H-fluoren-9-ylmethyl4-butoxy-3-{{(tert-butoxycarbonyl)-amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinylcarbamate(0.53 g, 82.8%) as crystals.

Melting point 137–138° C. Elemental analysis for C₃₈H₄₅N₃O₆ Calculated:C, 71.34; H, 7.09; N, 6.57. Found: C, 71.09; H, 7.03; N, 6.63.¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=7.0 Hz), 1.01 (3H, t, J=7.4 Hz), 1.46(9H, s), 1.47–1.61 (2H, m), 1.79–1.90 (2H, m), 2.09–2.23 (1H, m), 3.85(2H, t, J=6.4 Hz), 3.97 (2H, d, J=7.4 Hz), 4.28 (1H, t, J=6.2 Hz), 4.50(2H, d, J=5.2 Hz), 4.61 (2H, d, J=6.2 Hz), 4.80 (2H, bs), 7.11–7.16 (1H,m), 7.29–7.46 (4H, m), 7.63 (2H, d, J=7.0 Hz), 7.79 (2H, d, J=7.0 Hz),7.87 (1H, d, J=1.8 Hz), 8.32 (1H, d, J=8.8 Hz).

(2) To a solution of 9H-fluoren-9-ylmethyl4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinylcarbamate(0.45 g, 0.7 mmol) in N,N-dimethylformamide (10 ml) was addedpyrrolidine (0.5 ml) and the mixture was stirred at room temperature for1 h. The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.23 g, 79.3%) as crystals.

Melting point 175–176° C. Elemental analysis for C₂₃H₃₅N₃O₄ Calculated:C, 66.16; H, 8.45; N, 10.06. Found: C, 66.10; H, 8.74; N, 10.05.¹H-NMR(CDCl₃) δ: 0.94 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.4 Hz), 1.46(9H, s), 1.50–1.64 (2H, m), 1.77–1.91 (2H, m), 2.05–2.22 (1H, m), 3.82(2H, t, J=6.6 Hz), 3.93 (2H, d, J=7.2 Hz), 4.16 (2H, s), 4.47 (2H, d,J=5.4 Hz), 4.69 (1H, bs), 6.778–6.83 (2H, m), 8.21 (1H, d, J=9.2 Hz).

(3) 6-Amino-3-(aminomethyl)-4-butoxy-2-isobutyl-1(2H)-isoquinolinonedihydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 245–247° C. Elemental analysis for C₁₈H₂₉N₃O₂Cl₂Calculated: C, 55.38; H, 7.49; N, 10.76. Found: C, 55.02; H, 7.47; N,10.72. ¹H-NMR(DMSO-d₆) δ: 0.86 (6H, d, J=6.6 Hz), 0.99 (3H, t, J=7.4Hz), 1.44–1.63 (2H, m), 1.77–2.02 (3H, m), 3.84–3.90 (4H, m), 4.11 (2H,d, J=4.0 Hz), 6.30 (3H, bs), 6.91–7.01 (2H, m), 8.00 (1H, d, J=9.2 Hz),8.60 (3H, bs).

Example 833-(Aminomethyl)-6-bromo-4-butoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1) Ethyl6-bromo-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (1))

Melting point 105–106° C. Elemental analysis for C₁₇H₂₀NO₄Br Calculated:C, 53.42; H, 5.37; N, 3.66. Found: C, 53.75; H, 5.25; N, 3.61.¹H-NMR(CDCl₃) δ: 0.84 (9H, s), 1.47 (3H, t, J=7.2 Hz), 4.54 (2H, bs),7.78 (1H, dd, J=1.8, 8.4 Hz), 8.28 (1H, d, J=1.8 Hz), 8.30 (1H, d, J=8.4Hz), 10.72 (1H, s).

(2) Ethyl6-bromo-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 1 (2))

Melting point 107.5–108° C. Elemental analysis for C₂₁H₂₈NO₄BrCalculated: C, 57.54; H, 6.44; N, 3.20. Found: C, 57.54; H, 6.48; N,3.18. ¹H-NMR(CDCl₃) δ: 0.93 (9H, s), 1.02 (3H, t, J=7.3 Hz), 1.44 (3H,t, J=7.2 Hz), 1.44–1.61 (2H, m), 1.73–1.87 (2H, m), 3.94 (2H, t, J=6.6Hz), 4.06 (2H, bs), 4.43 (2H, q, J=7.2 Hz), 7.65 (1H, dd, J=2.0, 8.6Hz), 7.89 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=8.6 Hz).

(3)6-Bromo-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 4(3))

Melting point 152–153° C. Elemental analysis for C₁₉H₂₄NO₄Br Calculated:C, 55.62; H, 5.90; N, 3.41. Found: C, 55.58; H, 5.80; N, 3.35.¹H-NMR(CDCl₃) δ: 0.93 (9H, s), 1.01 (3H, t, J=7.3 Hz), 1.46–1.65 (2H,m), 1.76–1.90 (2H, m), 4.02 (2H, t, J=6.4 Hz), 4.22 (2H, bs), 6.50 (1H,bs), 7.67 (1H, dd, J=2.0, 8.6 Hz), 7.82 (1H, d, J=2.0 Hz), 8.21 (1H, d,J=8.6 Hz).

(4) 6-Bromo-4-butoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (4))

Melting point 162–163° C. Elemental analysis for C₁₉H₂₆NO₃Br Calculated:C, 57.58; H, 6.61; N, 3.53. Found: C, 57.60; H, 6.55; N, 3.49.¹-NMR(CDCl₃) δ: 0.95 (9H, s), 1.05 (3H, t, J=7.1 Hz), 1.51–1.69 (2H, m),1.80–1.93 (2H, m), 2.88 (1H, t, J=5.8 Hz), 3.88 (2H, t, J=6.4 Hz), 4.18(2H, bs), 4.86 (2H, bs), 7.49 (1H, dd, J=1.8, 8.8 Hz), 7.75 (1H, d,J=1.8 Hz), 8.08 (1H, d, J=8.8 Hz).

(5) 6-Bromo-4-butoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 4 (5))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.05 (3H, t, J=7.3 Hz), 1.52–1.70 (2H,m), 1.82–1.95 (2H, m), 3.94 (2H, t, J=6.4 Hz), 4.18 (2H, bs), 4.86 (2H,bs), 7.67 (1H, dd, J=1.8, 8.8 Hz), 7.87 (1H, d, J=1.8 Hz), 8.28 (1H, d,J=8.8 Hz).

(6)2-{(6-Bromo-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione(synthesized according to the method similar to that in Example 4 (6))

Melting point 134–136° C. Elemental analysis for C₂₇H₂₉N₂O₄BrCalculated: C, 61.72; H, 5.56; N, 5.33. Found: C, 61.92; H, 5.49; N,5.32. ¹H-NMR(CDCl₃) δ: 1.02 (9H, s), 1.02 (3H, t, J=7.3 Hz), 1.46–1.65(2H, m), 1.82–1.96 (2H, m), 4.01 (2H, t, J=6.8 Hz), 4.05 (2H, bs), 5.07(2H, s), 7.58 (1H, dd, J=2.0, 8.6 Hz), 7.60–7.84 (4H, m), 7.87 (1H, d,J=2.0 Hz), 8.25 (1H, d, J=8.6 Hz).

(7)Tert-butyl(6-bromo-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 1 (6))

Melting point 130–131° C. Elemental analysis for C₂₄H₃₅N₂O₄BrCalculated: C, 58.18; H, 7.12; N, 5.65. Found: C, 58.50; H, 7.09; N,5.56. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.4 Hz), 1.45 (9H,s), 1.46–1.68 (2H, m), 1.80–1.93 (2H, m), 3.85 (2H, t, J=6.4 Hz), 4.14(2H, bs), 4.56 (2H, d, J=5.4 Hz), 4.71 (1H, bs), 7.58 (1H, dd, J=1.8,8.4 Hz), 7.82 (1H, d, J=1.8 Hz), 8.24 (1H, d, J=8.4 Hz).

(8) 3-(Aminomethyl)-6-bromo-4-butoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 114–115° C. Elemental analysis for C₁₉H₂₈N₂O₂BrClCalculated: C, 52.85; H, 6.54; N, 6.49. Found: C, 52.60; H, 6.62; N,6.44. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.4 Hz), 1.46–1.64(2H, m), 1.77–1.90 (2H, m), 3.94 (2H, t, J=6.0 Hz), 4.12 (2H, bs), 4.24(2H, s), 7.79 (1H, dd, J=1.8, 8.4 Hz), 7.87 (1H, d, J=1.8 Hz), 8.19 (1H,d, J=8.4 Hz), 8.52 (3H, bs).

Example 84 Methyl3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride

(1) Methyl4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(synthesized according to the method similar to that in Example 75 (1))

Elemental analysis for C₂₆H₃₈N₂O₆ Calculated: C, 65.80; H, 8.07; N,5.90. Found: C, 66.03; H, 8.33; N, 6.05. ¹H-NMR(CDCl₃) δ: 1.00 (9H, s),10.6 (3H, t, J=7.4 Hz), 1.46 (9H, S), 1.53–1.71 (2H, m), 1.83–1.97 (2H,m), 3.90 (2H, t, J=6.4 Hz), 3.99 (3H, s), 4.14 (2H, bs), 4.59 (2H, d,J=5.4 Hz), 4.79 (1H, bs), 8.06 (1H, dd, J=1.7, 8.4 Hz), 8.38 (1H, d,J=1.7 Hz), 8.43 (1H, d, J=8.4 Hz).

(2) Methyl3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 123–124° C. Elemental analysis for C₂₁H₃₁N₂O₄ClCalculated: C, 61.38; H, 7.60; N, 6.82. Found: C, 61.08; H, 7.82; N,6.82. ¹H-NMR(DMSO-d₆) δ: 0.92 (9H, s), 1.02 (3H, t, J=7.3 Hz), 1.55–1.66(2H, m), 1.79–1.91 (2H, m), 3.95 (3H, s), 3.97 (2H, t, J=6.2 Hz), 4.14(2H, bs), 4.28 (2H, s), 8.11 (1H, dd, J=1.6, 8.6 Hz), 8.34 (1H, d, J=1.6Hz), 8.40 (1H, d, J=8.6 Hz), 8.56 (3H, bs).

Example 853-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid hydrochloride

(1)4-Butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (synthesized according to the method similar to that in Example 76(1))

Melting point 130–131° C. Elemental analysis for C₂₅H₃₆N₂O₆ Calculated:C, 65.20; H, 7.88; N, 6.08. Found: C, 64.92; H, 7.88; N, 6.04.¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.08 (3H, t, J=7.3 Hz), 1.50 (9H, S),1.56–1.73 (2H, m), 1.85–1.99 (2H, m) 3.90 (2H, t, J=6.2 Hz), 4.14 (2H,bs), 4.61 (2H, d, J=5.2 Hz), 5.64 (1H, bs), 8.31 (1H, d, J=8.4 Hz),8.28–8.33 (2H, m).

(2)3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid hydrochloride (synthesized according to the method similar to thatin Example 1 (7))

Melting point 255–257° C. Elemental analysis for C₂₀H₂₉N₂O₄ClCalculated: C, 60.52; H, 7.36; N, 7.06. Found: C, 60.42; H, 7.35; N,7.01. ¹H-NMR(DMSO-d₆) δ: 0.92 (9H, s), 1.01 (3H, t, J=7.4 Hz), 1.54–1.66(2H, m), 1.79–1.92 (2H, m), 3.97 (2H, t, J=6.3 Hz), 4.13 (2H, bs), 4.28(2H, s), 8.09 (1H, dd, J=1.5, 8.4 Hz), 8.33 (1H, bs), 8.34 (1H, d, J=1.5Hz), 8.38 (1H, d, J=8.4 Hz), 8.60 (3H, bs).

Example 863-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamidehydrochloride

(1)Tert-butyl{(6-aminocarbonyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 77 (1))

Melting point 172–173° C. Elemental analysis for C₂₅H₃₇N₃O₅ ½(i-Pr)₂OCalculated: C, 65.86; H, 8.49; N, 8.23. Found: C, 65.53; H, 8.75; N,8.17. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s) 1.04 (3H, t, J=7.2 Hz), 1.46 (9H,S), 1.47–1.68 (2H, m), 1.81–1.95 (2H, m), 3.71 (2H, t, J=6.2 Hz), 4.14(2H, bs), 4.58 (2H, d, J=5.6 Hz), 4.97 (1H, bs), 5.91 (1H, bs), 6.39(1H, bs), 7.75 (1H, dd, J=1.6, 8.4 Hz), 8.12 (1H, d, J=8.4 Hz), 8.36(1H, d, J=8.4 Hz).

(2)3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 237–238° C. Elemental analysis for C₂₀H₃₀N₃O₃Cl ½H₂OCalculated: C, 59.32; H, 7.72; N 10.38. Found: C, 59.45; H, 7.63; N,10.20. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 1.00 (3H, t, J=7.4 Hz),1.48–1.67 (2H, m), 1.80–1.92 (2H, m), 3.98 (2H, t, J=6.4 Hz), 4.12 (2H,bs), 4.26 (2H, s), 7.70 (1H, s), 8.04 (1H, dd, J=1.2, 8.2 Hz), 8.22 (1H,d, J=1.2 Hz), 8.33 (1H, d, J=8.2 Hz), 8.37 (1H, s), 8.58 (3H, bs).

Example 873-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarbonitrilehydrochloride

(1)Tert-butyl(4-butoxy-6-cyano-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 78 (7))

Melting point 162–163° C. Elemental analysis for C₂₅H₃₅N₃O₄ Calculated:C, 68.00; H, 7.99; N, 9.52. Found: C, 67.97; H, 8.13; N, 9.44.¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.05 (3H, t, J=7.3 Hz), 1.45 (9H, s),1.53–1.68 (2H, m), 1.82–1.90 (2H, m), 3.86 (2H, t, J=6.6 Hz), 4.17 (2H,bs), 4.58 (2H, d, J=5.4 Hz), 4.70 (1H, bs), 7.68 (1H, dd, J=1.6, 8.8Hz), 8.00 (1H, d, J=1.6 Hz), 8.49 (1H, d, J=8.2 Hz)

(2)3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarbonitrilehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₂₀H₂₈N₃O₂Cl ¼H₂O Calculated: C, 62.81; H, 7.51;N, 10.99. Found: C, 62.98; H, 7.75; N, 10.95. ¹H-NMR(DMSO-d₆) δ: 0.91(9H, s), 1.00 (3H, t, J=7.1 Hz), 1.46–1.64 (2H, m), 1.80–1.92 (2H, m),3.97 (2H, t, J=6.4 Hz), 4.14 (2H, bs), 4.27 (2H, bs), 7.97 (1H, dd,J=1.2, 8.0 Hz), 8.23 (1H, d, J=1.2 Hz), 8.41 (1H, d, J=8.0 Hz), 8.68(3H, bs).

Example 88N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}acetamidehydrochloride

(1) A solution oftert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 82 (2))(0.21 g, 0.5 mmol) and acetyl chloride (0.04 ml, 0.6 mmol) inN,N-dimethylacetamide (10 ml) was stirred at room temperature for 2 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas recrystallized from ethyl acetate-diisopropyl ether to givetert-butyl{6-(acetylamino)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.19 g, 80.8%) as crystals.

Melting point 174–175° C. Elemental analysis for C₂₅H₃₇N₃O₅ Calculated:C, 65.34; H, 8.11; N, 9.14. Found: C, 65.32; H, 8.05; N, 9.21.¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.4 Hz), 1.47(9H, S), 1.47–1.65 (2H, m), 1.81–1.95 (2H, m), 2.09–2.20 (1H, m), 2.26(3H, s), 3.88 (2H, t, J=6.6 Hz), 3.98 (2H, d, J=7.4 Hz), 4.51 (2H, d,J=5.6 Hz), 4.82 (1H, bs), 7.35 (1H, d, J=8.0 Hz), 7.71 (1H, bs), 8.17(1H, s), 8.32 (1H, d, J=8.0 Hz).

(2)N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}acetamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 176–177° C. Elemental analysis for C₂₀H₃₀N₃O₃Cl H₂OCalculated: C, 58.03; H, 7.79; N, 10.15. Found: C, 58.26; H, 8.11; N,10.08. ¹H-NMR(DMSO-d₆) δ: 0.87 (6H, d, J=6.6 Hz), 0.99 (3H, t, J=7.3Hz), 1.50–1.62 (2H, m), 1.79–2.04 (3H, m), 2.14 (3H, s), 3.91 (2H, t,J=6.8 Hz), 3.93 (2H, d, J=7.0 Hz), 4.16 (2H, d, J=5.4 Hz), 7.70 (1H, dd,J=2.0, 8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.27 (1H, d, J=2.0 Hz), 8.56(3H, bs), 10.59 (1H, s).

Example 89N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}propanamidehydrochloride

(1)tert-butyl{4-butoxy-2-isobutyl-1-oxo-6-(propionylamino)-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 88 (1))

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=7.0 Hz), 1.01 (3H, t, J=7.2 Hz), 1.28(3H, t, J=7.6 Hz), 1.46 (9H, S), 1.47–1.67 (2H, m), 1.80–1.94 (2H, m),2.09–2.27 (1H, m), 2.48 (2H, q, J=7.6 Hz), 3.88 (2H, t, J=6.4 Hz), 3.98(2H, d, J=7.4 Hz), 4.51 (2H, d, J=5.0 Hz), 4.83 (1H, bs), 7.37 (1H, dd,J=1.8, 8.8 Hz), 7.69 (1H, bs), 8.15 (1H, d, J=1.8 Hz), 8.31 (1H, d,J=8.8 Hz).

(2)N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}propanamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

¹H-NMR(DMSO-d₆) δ: 0.87 (6H, d, J=7.0 Hz), 1.00 (6H, m), 1.46–1.64 (2H,m), 1.72–2.14 (3H, m), 2.41–2.50 (2H, m), 3.91 (4H, bs), 4.16 (2H, s),7.72 (1H, d, J=9.0 Hz), 8.18 (1H, d, J=9.0 Hz), 8.27 (1H, s), 8.55 (3H,bs), 10.49 (1H, s).

Example 90N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}-2-methylpropanamidehydrochloride

(1)Tert-butyl{4-butoxy-2-isobutyl-6-(isobutyrylamino)-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 88 (1))

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=7.0 Hz), 1.02 (3H, t, J=7.2 Hz), 1.29(6H, d, J=7.0 Hz), 1.46 (9H, S), 1.47–1.66 (2H, m), 1.80–1.91 (2H, m),2.09–2.20 (1H, m), 2.53–2.66 (1H, m), 3.89 (2H, t, J=6.6 Hz), 3.98 (2H,d, J=7.4 Hz), 4.51 (2H, d, J=5.6 Hz), 4.79 (1H, bs), 7.41 (1H, dd,J=1.8, 8.8 Hz), 7.62 (1H, bs), 8.15 (1H, d, J=1.8 Hz), 8.32 (1H, d,J=8.8 Hz).

(2)N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}-2-methylpropanamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 181–183° C. ¹H-NMR(DMSO-d₆) δ: 0.88 (6H, d, J=6.2 Hz),1.00 (3H, t, J=7.4 Hz), 1.14 (6H, d, J=6.6 Hz), 1.48–1.64 (2H, m),1.83–2.12 (3H, m), 2.62–2.78 (1H, m), 3.92–3.95 (4H, m), 4.16 (2H, bs),7.76 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.27 (1H, s), 8.57 (3H,bs), 10.47 (1H, s).

Example 91N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}benzamidehydrochloride

(1)Tert-butyl{4-butoxy-6-(benzoylamino)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 88 (1))

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.4 Hz), 1.47(9H, S), 1.48–1.68 (2H, m), 1.82–1.96 (2H, m), 2.07–2.23 (1H, m), 3.92(2H, t, J=6.8 Hz), 3.98 (2H, d, J=8.8 Hz), 4.52 (2H, d, J=5.4 Hz), 4.89(1H, bs), 7.45–7.62 (4H, m), 7.90–7.94 (2H, m), 8.25 (1H, bs), 7.56 (1H,bs), 8.27 (1H, d, J=1.8 Hz), 8.32 (1H, d, J=8.8 Hz).

(2)N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}benzamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.01 (3H, t, J=7.3 Hz),1.49–1.67 (2H, m), 1.83–2.06 (3H, m), 3.93–3.98 (4H, m), 4.19 (2H, s),7.54–7.68 (3H, m), 7.95–8.03 (3H, m), 8.25 (1H, d, J=8.8 Hz), 8.43 (1H,d, J=1.8 Hz), 8.58 (3H, bs), 10.77 (1H, s).

Example 92N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}cyclopentanecarboxamidehydrochloride

(1)Tert-butyl{4-butoxy-6-{(cyclopentylcarbonyl)amino}-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 88 (1))

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=7.0 Hz), 1.02 (3H, t, J=7.3 Hz), 1.46(9H, S), 1.47–1.74 (4H, m), 1.78–2.20 (9H, m), 2.67–2.80 (1H, m), 3.89(2H, t, J=6.6 Hz), 3.98 (2H, d, J=7.6 Hz), 4.51 (2H, d, J=5.4 Hz), 4.78(1H, bs), 7.42 (1H, dd, J=2.2, 8.8 Hz), 7.56 (1H, bs), 8.12 (1H, d,J=2.2 Hz), 8.32 (1H, d, J=8.8 Hz).

(2)N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}cyclopentanecarboxamide(synthesized according to the method similar to that in Example 1(7))

¹H-NMR(DMSO-d₆) δ: 0.87 (6H, d, J=6.2 Hz), 0.99 (3H, t, J=7.1 Hz),1.54–2.11 (11H, m), 2.79–2.92 (1H, m), 3.91–3.95 (4H, m), 4.16 (2H, s),7.75 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.25 (1H, s), 8.55 (3H,bs), 10.49 (1H, s).

Example 93N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}methanesulfonamidehydrochloride

(1)Tert-butyl{4-butoxy-2-isobutyl-6-{(methylsulfonyl)amino}-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 88 (1))

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.4 Hz), 1.47(9H, s), 1.47–1.64 (2H, m), 1.79–1.94 (2H, m), 2.10–2.23 (1H, m), 3.11(3H, s), 3.86 (2H, t, J=6.6 Hz), 3.99 (2H, d, J=7.8 Hz), 4.51 (2H, d,J=5.4 Hz), 4.77 (1H, bs), 7.23 (1H, dd, J=2.0, 8.6 Hz), 7.31 (1H, s),7.56 (1H, d, J=2.0 Hz), 8.38 (1H, d, J=8.6 Hz).

(2)N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}methanesulfonamide(synthesized according to the method similar to that in Example 1 (7))

¹H-NMR(DMSO-d₆) δ: 0.87 (6H, d, J=6.6 Hz), 0.99 (3H, t, J=7.8 Hz),1.45–1.64 (2H, m), 1.78–2.09 (3H, m), 3.13 (3H, s), 3.88–3.94 (4H, m),4.17 (2H, bs), 7.40 (1H, dd, J=2.0, 8.8 Hz), 7.60 (1H, d, J=2.0 Hz),8.21 (1H, d, J=8.8 Hz), 8.58 (3H, bs), 10.57 (1H, s).

Example 94N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}benzenesulfonamidehydrochloride

(1)Tert-butyl{4-butoxy-2-isobutyl-1-oxo-6-{(phenylsulfonyl)amino}-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 88 (1))

Melting point 160–161° C. Elemental analysis for C₂₉H₃₉N₃O₆S Calculated:C, 62.45; H, 7.05; N, 7.53. Found: C, 62.35; H, 6.97; N, 7.50.¹H-NMR(CDCl₃) δ: 0.93 (6H, d, J=6.6 Hz) 1.02 (3H, t, J=7.3 Hz), 1.46(9H, s), 1.47–1.63 (2H, m), 1.72–1.90 (2H, m), 2.07–2.20 (1H, m), 3.76(2H, t, J=6.6 Hz), 3.96 (2H, d, J=7.6 Hz), 4.48 (2H, d, J=5.6 Hz), 4.78(1H, bs), 7.14 (1H, d, J=8.4 Hz), 7.41–7.58 (4H, m), 7.81–7.99 (3H, m),8.25 (1H, dd, J=1.4, 8.4 Hz).

(2)N-{3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl}benzenesulfonamide(synthesized according to the method similar to that in Example 1 (7))

Melting point 166–167° C. Elemental analysis for C₂₄H₃₂N₃O₄ClS ¼H₂OCalculated: C, 57.82; H, 6.57; N, 8.43. Found: C, 57.83; H, 6.49; N,8.26. ¹H-NMR(DMSO-d₆) δ: 0.84 (6H, d, J=7.4 Hz), 1.01 (3H, t, J=7.4 Hz),1.43–1.62 (2H, m), 1.75–1.99 (3H, m), 3.76 (2H, t, J=6.6 Hz), 3.89 (2H,d, J=6.8 Hz), 4.11 (2H, bs), 7.35 (1H, dd, J=2.0, 8.6 Hz), 7.53–7.65(3H, m), 7.83–7.88 (2H, m), 8.13 (1H, d, J=8.6 Hz), 8.52 (3H, bs), 11.18(1H, s).

Example 952-{{3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl}oxy}acetamidehydrochloride

(1) A solution oftert-butyl(4-butoxy-6-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(Example 59 (1)) (0.43 g, 1 mmol), iodoacetamide (0.22 g, 1.2 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.18 ml, 1.2 mmol) inN,N-dimethylformamide (10 ml) was stirred at 70° C. for 12 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-diisopropyl ether to givetert-butyl{6-(2-amino-2-oxoethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}-methylcarbamate(0.29 g, 60.4%) as crystals.

Melting point 114–115° C. Elemental analysis for C₂₆H₃₉N₃O₆ Calculated:C, 63.78; H, 8.03; N, 8.58. Found: C, 63.61; H, 7.91; N, 8.43.¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.0 Hz), 1.43 (9H, S),1.45–1.67 (2H, m), 1.79–1.90 (2H, m), 3.85 (2H, t, J=6.6 Hz), 4.14 (2H,bs), 4.56 (2H, d, J=5.4 Hz), 4.57 (1H, bs), 7.07–7.12 (2H, m), 8.36 (1H,d, J=9.4 Hz).

(2)2-{{3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl}oxy}acetamidehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 233–235° C. Elemental analysis for C₂₁H₃₂N₃O₄Cl ½H₂OCalculated: C, 57.99; H, 7.65; N, 9.66. Found: C, 58.18; H, 7.68; N,9.63. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.50–1.65(2H, m), 1.77–1.91 (2H, m), 3.92 (2H, t, J=6.4 Hz), 4.07 (2H, bs), 4.22(2H, d, J=4.4 Hz), 4.64 (2H, s), 7.07 (1H, d, J=2.6 Hz), 7.22 (1H, dd,J=2.6, 8.8 Hz), 7.46 (1H, bs), 7.73 (1H, bs), 8.20 (1H, d, J=8.8 Hz),8.54 (3H, bs).

Example 963-(Aminomethyl)-4-butoxy-6-isopropoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl(4-butoxy-6-isopropoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 95 (1))

Melting point 130–130.5° C. Elemental analysis for C₂₇H₄₂N₂O₅Calculated: C, 68.32; H, 8.92; N, 5.90. Found: C, 68.28; H, 8.75; N,5.99. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.03 (3H, t, J=7.4 Hz), 1.41 (6H,d, J=5.8 Hz), 1.45 (9H, s), 1.46–1.65 (2H, m), 1.79–1.93 (2H, m), 3.86(2H, t, J=6.4 Hz), 4.14 (2H, bs), 4.55 (2H, d, J=4.8 Hz), 4.64–4.76 (2H,m), 7.00–7.04 (2H, m), 8.31 (1H, d, J=9.6 Hz).

(2)3-(Aminomethyl)-4-butoxy-6-isopropoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 181–182° C. Elemental analysis for C₂₂H₃₅N₂O₃ClCalculated: C, 64.29; H, 8.58; N, 6.82. Found: C, 64.10; H, 8.80; N,6.78. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.1 Hz), 1.35 (6H,d, J=6.2 Hz), 1.51–1.62 (2H, m), 1.77–1.90 (2H, m), 3.93 (2H, t, J=6.3Hz), 4.07 (2H, bs), 4.22 (2H, bs), 4.74–4.86 (1H, m), 7.05 (1H, d, J=2.4Hz), 7.16 (1H, dd, J=2.4, 8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.52 (3H,bs).

Example 973-(Aminomethyl)-4-butoxy-2-neopentyl-6-(2,2,2-trifluoroethoxy)-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl{4-butoxy-2-neopentyl-6-(2,2,2-trifluoroethoxy)-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 95 (1))

Melting point 154.5–155° C. Elemental analysis for C₂₆H₃₇N₂O₅F₃Calculated: C, 60.69; H, 7.25; N, 5.44. Found: C, 60.44; H, 7.16; N,5.48. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.0 Hz), 1.45 (9H,s), 1.46–1.64 (2H, m), 1.80–1.90 (2H, m), 3.86 (2H, t, J=6.6 Hz), 4.11(2H, bs), 4.48 (2H, q, J=8.0 Hz), 4.56 (2H, d, J=5.6 Hz), 4.71 (1H, bs),7.09–7.13 (2H, m), 8.37 (1H, d, J=8.0 Hz).

(2)3-(Aminomethyl)-4-butoxy-2-neopentyl-6-(2,2,2-trifluoroethoxy)-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 145.5–146° C. Elemental analysis for C₂₁H₃₀N₂O₃ClF₃ ½H₂OCalculated: C, 54.84; H, 6.79; N, 6.09. Found: C, 54.75; H, 6.77; N,6.22. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 0.99 (3H, t, J=7.3 Hz), 1.47–1.65(2H, m), 1.78–1.89 (2H, m), 3.95 (2H, t, J=6.4 Hz), 4.08 (2H, bs), 4.24(2H, bs), 5.02 (2H, q, J=8.8 Hz), 7.18 (1H, d, J=2.6 Hz), 7.32 (1H, dd,J=2.6, 8.8 Hz), 8.24 (1H, d, J=8.8 Hz), 8.52 (3H, bs).

Example 983-(Aminomethyl)-4-butoxy-6-(cyclopropylmethoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl{4-butoxy-6-(cyclopropylmethoxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 95 (1))

Melting point 154–155° C. Elemental analysis for C₂₈H₄₂N₂O₅ ½H₂OCalculated: C, 67.85; H, 8.74; N, 5.65. Found: C, 68.08; H, 8.65; N,5.47. ¹H-NMR(CDCl₃) δ: 0.36–0.42 (2H, m), 0.65–0.75 (2H, m), 0.99 (9H,s), 1.03 (3H, t, J=7.4 Hz), 1.22–1.37 (1H, m), 1.45 (9H, s), 1.52–1.68(2H, m), 1.78–1.93 (2H, m), 3.86 (2H, t, J=6.4 Hz), 3.92 (2H, d, J=6.8Hz), 4.10 (2H, bs), 4.55 (2H, d, J=5.2 Hz), 4.63 (1H, bs), 7.04–7.10(2H, m), 8.30–8.34 (1H, m).

(2)3-(Aminomethyl)-4-butoxy-6-(cyclopropylmethoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Melting point 203–205° C. Elemental analysis for C₂₃H₃₅N₂O₃ClCalculated: C, 65.31; H, 8.34; N, 6.62. Found: C, 65.23; H, 8.25; N,6.71. ¹H-NMR(DMSO-d₆) δ: 0.34–0.42 (2H, m), 0.58–0.67 (2H, m), 0.89 (9H,s), 0.99 (3H, t, J=7.3 Hz), 1.23–1.33 (1H, m), 1.52–1.63 (2H, m),1.77–1.87 (2H, m), 3.93 (2H, t, J=6.2 Hz), 3.99 (2H, d, J=7.0 Hz), 4.03(2H, bs), 4.23 (2H, s), 7.06 (1H, d, J=2.4 Hz), 7.19 (1H, dd, J=2.4, 9.0Hz), 8.18 (1H, d, J=9.0 Hz), 8.50 (3H, bs).

Example 993-(Aminomethyl)-4-butoxy-2-neopentyl-6-(2-propynyloxy)-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl{4-butoxy-2-neopentyl-1-oxo-6-(2-propynyloxy)-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 95 (1))

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.03 (3H, t, J=7.4 Hz), 1.45 (9H, s),1.53–1.68 (2H, m) 1.80–1.94 (2H, m), 2.57 (1H, t, J=2.2 Hz), 3.87 (2H,t, J=6.4 Hz), 4.10 (2H, bs), 4.56 (2H, d, J=4.8 Hz), 4.63 (1H, bs), 4.82(2H, d, J=2.2 Hz), 7.11 (1H, dd, J=2.4, 8.8 Hz), 7.19 (1H, d, J=2.4 Hz),8.35 (1H, d, J=8.8 Hz).

(2)3-(Aminomethyl)-4-butoxy-2-neopentyl-6-(2propynyloxy)-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7)))

Elemental analysis for C₂₂H₃₁N₂O₃Cl ¼H₂O Calculated: C, 64.22; H, 7.72;N, 6.81. Found: C, 64.36; H, 7.73; N, 6.66. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H,s), 1.00 (3H, t, J=7.4 Hz), 1.53–1.64 (2H, m), 1.79–1.91 (2H, m) 3.71(1H, t, J=2.2 Hz), 3.95 (2H, t, J=6.1 Hz), 4.08 (2H, bs), 4.23 (2H, s),5.01 (1H, d, J=2.2 Hz), 7.19–7.23 (2H, m), 8.20 (1H, d, J=9.6 Hz), 8.50(3H, bs).

Example 1003-(Aminomethyl)-4-butoxy-6-isobutoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl(4-butoxy-6-isobutoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(synthesized according to the method similar to that in Example 95 (1))

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.2 Hz), 1.06 (6H, d,J=6.4 Hz), 1.45 (9H, s), 1.51–1.69 (2H, m), 1.79–1.93 (2H, m), 2.09–2.22(1H, m), 3.84 (2H, d, J=6.6 Hz), 3.86 (2H, t, J=6.5 Hz), 4.10 (2H, bs),4.56 (2H, d, J=5.6 Hz), 4.69 (1H, bs), 7.04–7.08 (2H, m), 8.31 (1H, d,J=9.4 Hz).

(2)3-(Aminomethyl)-4-butoxy-6-isobutoxy-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₂₃H₃₇N₂O₃Cl ¼H₂O Calculated: C, 64.32; H, 8.80;N, 6.52. Found: C, 64.31; H, 8.87; N, 6.60. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H,s), 1.00 (3H, t, J=7.0 Hz), 1.02 (6H, d, J=6.6 Hz), 1.50–1.68 (2H, m),1.77–1.87 (2H, m), 2.03–2.16 (1H, m), 3.92 (2H, d, J=6.6 Hz), 3.93 (2H,t, J=6.2 Hz), 4.04 (2H, bs), 4.23 (2H, s), 7.07 (1H, d, J=2.6 Hz), 7.19(1H, dd, J=2.6, 8.8 Hz), 8.18 (1H, d, J=8.8 Hz) 8.45 (3H, bs).

Example 1013-(Aminomethyl)-4-butoxy-6-(cyclopentyloxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl{4-butoxy-6-(cyclopentyloxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 95 (1))

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.03 (3H, t, J=7.4 Hz), 1.45 (9H, s),1.50–1.70 (4H, m), 1.73–1.98 (8H, m), 3.86 (2H, t, J=6.4 Hz), 4.10 (2H,bs), 4.55 (2H, d, J=5.2 Hz), 4.68 (1H, bs), 4.86–4.90 (1H, m), 6.98–7.04(2H, m), 8.27–8.32 (1H, m).

(2)3-(Aminomethyl)-4-butoxy-6-(cyclopentyloxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₂₄H₃₇N₂O₃Cl ¼H₂O Calculated: C, 65.29; H, 8.56;N, 6.34. Found: C, 65.27; H, 8.53; N, 6.18. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H,s), 1.00 (3H, t, J=7.3 Hz), 1.52–2.05 (12H, m), 3.93 (2H, t, J=6.2 Hz),4.05 (2H, bs), 4.23 (2H, s), 4.99 (1H, bs), 7.04 (1H, d, J=2.4 Hz), 7.13(1H, dd, J=2.4, 9.0 Hz), 8.16 (1H, d, J=9.0 Hz), 8.51 (3H, bs).

Example 1023-(Aminomethyl)-4-butoxy-6-(cyclohexylmethoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl{4-butoxy-6-(cyclohexylmethoxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 95 (1))

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.3 Hz), 1.07–1.35 (3H,m), 1.45 (9H, s), 1.51–1.93 (8H, m), 3.83–3.89 (4H, m), 4.10 (2H, bs),4.55 (2H, d, J=5.2 Hz), 4.63 (1H, bs), 7.03–7.08 (2H, m), 8.31 (1H, d,J=8.4 Hz).

(2)3-(Aminomethyl)-4-butoxy-6-(cyclohexylmethoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₂₆H₄₁N₂O₃Cl Calculated: C, 67.15; H, 8.89; N,6.02. Found: C, 67.00; H, 8.83; N, 6.03. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H,s), 1.00 (3H, t, J=7.3 Hz), 1.09–1.30 (3H, m), 1.53–1.84 (12H, m),3.90–3.97 (4H, m), 4.08 (2H, bs), 4.23 (2H, s), 7.06 (1H, d, J=2.3 Hz),7.18 (1H, dd, J=2.3, 8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.47 (3H, bs).

Example 1033-(Aminomethyl)-4-butoxy-6-(3,3-dimethyl-2-oxobutoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl{4-butoxy-6-(3,3-dimethyl-2-oxobutoxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 95 (1))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.03 (3H, t, J=7.2 Hz), 1.29 (9H, s),1.45 (9H, s), 1.51–1.65 (2H, m), 1.76–1.87 (2H, m), 3.87 (2H, t, J=6.4Hz), 4.10 (2H, bs), 4.54 (2H, d, J=5.2 Hz), 4.69 (1H, bs), 5.01 (2H, s),6.98 (1H, d, J=2.6 Hz), 7.05 (1H, dd, J=2.6, 8.8 Hz), 8.33 (1H, d, J=8.8Hz).

(2)3-(Aminomethyl)-4-butoxy-6-(3,3-dimethyl-2-oxobutoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₂₅H₃₉N₂O₄Cl ¼H₂O Calculated: C, 63.68; H, 8.44;N, 5.94. Found: C, 63.64; H, 8.32; N, 5.99. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H,s), 0.98 (3H, t, J=7.2 Hz), 1.21 (9H, s), 1.48–1.59 (2H, m), 1.73–1.84(2H, m), 3.90 (2H, t, J=6.5 Hz), 4.05 (2H, bs), 4.21 (2H, s), 5.39 (2H,s), 6.90 (1H, d, J=2.5 Hz), 7.17 (1H, dd, J=2.5, 8.9 Hz), 8.18 (1H, d,J=8.9 Hz), 8.43 (3H, bs).

Example 104 Ethyl{{3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl}oxy}acetatehydrochloride

(1) Ethyl{4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl}oxy}acetate(synthesized according to the method similar to that in Example 95 (1))

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.04 (3H, t, J=7.3 Hz), 1.30 (3H, t,J=7.1 Hz), 1.45 (9H, s), 1.52–1.67 (4H, m), 1.78–1.88 (2H, m), 3.84 (2H,t, J=6.6 Hz), 4.14 (2H, bs), 4.29 (2H, q, J=7.1 Hz), 4.55 (2H, d, J=5.2Hz), 4.64 (1H, bs), 4.74 (2H, s), 7.02 (1H, d, J=1.5 Hz), 7.08 (1H, dd,J=1.5, 8.8 Hz), 8.33 (1H, d, J=8.8 Hz).

(2) Ethyl{{3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl}oxy}acetatehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₂₃H₃₅N₂O₅Cl ½H₂O Calculated: C, 59.54; H, 7.82;N, 6.04. Found: C, 59.81; H, 7.70; N, 5.99. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H,s), 1.00 (3H, t, J=7.1 Hz), 1.23 (3H, t, J=7.1 Hz), 1.50–1.61 (4H, m),1.78–1.91 (2H, m), 3.91 (2H, t, J=6.2 Hz), 4.01 (2H, bs), 4.19 (2H, q,J=7.1 Hz), 4.21 (2H, s), 5.01 (2H, s), 6.99 (1H, d, J=2.6 Hz), 7.22 (1H,dd, J=2.6, 9.0 Hz), 8.20 (1H, d, J=9.0 Hz), 8.42 (3H, bs).

Example 1053-(Aminomethyl)-4-butoxy-6-(1-methyl-2-oxopropoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl{4-butoxy-6-(1-methyl-2-oxopropoxy)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(synthesized according to the method similar to that in Example 95 (1))32–11

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.3 Hz), 1.44 (9H, s),1.52–1.70 (5H, m), 1.78–1.92 (2H, m), 2.19 (3H, s), 3.89 (2H, t, J=6.4Hz), 4.11 (2H, bs), 4.57 (2H, d, J=5.4 Hz), 4.73 (1H, bs), 7.08–7.17(2H, m), 8.38 (1H, d, J=8.8 Hz).

(2)3-(Aminomethyl)-4-butoxy-6-(1-methyl-2-oxopropoxy)-2-neopentyl-1(2H)-isoquinolinonehydrochloride (synthesized according to the method similar to that inExample 1 (7))

Elemental analysis for C₂₃H₃₅N₂O₄Cl Calculated: C, 62.93; H, 8.04; N,6.38. Found: C, 62.70; H, 8.29; N, 6.39. ¹H-NMR(DMSO-d₆) δ: 0.89 (9H,s), 0.99 (3H, t, J=7.3 Hz), 1.48–1.60 (5H, m), 1.75–1.85 (2H, m), 2.20(3H, s), 3.83–4.05 (4H, m), 4.21 (2H, bs), 5.15 (2H, q, J=7.0 Hz), 6.90(1H, d, J=2.6 Hz), 7.18 (1H, dd, J=2.6, 8.8 Hz), 8.19 (1H, d, J=8.8 Hz),8.45 (3H, bs).

Example 1063-Aminomethyl-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone

(1) To a solution of 4-bromophthalic anhydride (50 g, 220 mmol) inbenzene (500 mL) was added aluminum chloride (60 g, 450 mmol) by smallportions under ice-cooling. The obtained mixture was stirred at roomtemperature for 24 h. The reaction mixture was poured into ice water andextracted with a mixed solvent of ethyl acetate-tetrahydrofuran (1/1).The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography and recrystallized fromethyl acetate-diisopropyl ether. The precipitated crystals werecollected by filtration to give 2-benzoyl-4-bromobenzoic acid (33 g,49%)as crystals.

Melting point 185–187° C. ¹H-NMR(CDCl₃) δ: 7.36–7.73 (7H, m), 7.94 (1H,d, J=8.4 Hz).

(2) A mixture of 2-benzoyl-4-bromobenzoic acid (25 g, 82 mmol),potassium carbonate (12 g, 87 mmol), diethyl bromomalonate (22 g, 92mmol), acetone (450 mL) and N,N-dimethylformamide (8 mL) was stirred atroom temperature for 15 h. The solvent was evaporated under reducedpressure. The residue was poured into water and extracted with ethylacetate. The residue was crystallized from hexane and the crystals werecollected by filtration. The obtained crystals were added to a mixtureof acetic acid (235 mL) and concentrated hydrochloric acid (360 mL) andthe mixture was stirred at 120° C. for 8 h. The reaction mixture wascooled and concentrated. The residue was poured into water and extractedwith ethyl acetate. The extract was washed with brine, dried withanhydrous sodium sulfate and concentrated under reduced pressure. Theprecipitated crystals were collected by filtration, washed withdiisopropyl ether and dried to give6-bromo-4-phenyl-1H-isochromene-3-carboxylic acid (17 g, 60%) ascrystals.

Melting point 205–206° C. ¹H-NMR(CDCl₃) δ: 7.20–7.28 (3H, m), 7.47–7.55(3H, m), 7.77 (1H, dd, J=8.6, 1.8 Hz), 8.26 (1H, d, J=8.6 Hz).

(3) A solution of 6-bromo-4-phenyl-1H-isochromene-3-carboxylic acid (8.0g, 23 mmol) and isobutylamine (23 mL, 230 mmol) in methanol (120 mL) wasstirred at room temperature for 15 h. The solvent was evaporated underreduced pressure, and the residue was acidified with concentratedhydrochloric acid and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. To the residue was added a solutionof 4N hydrogen chloride in ethyl acetate (150 mL) and the mixture wasstirred at room temperature for 3 h. The solvent was evaporated underreduced pressure, and the precipitated crystals were collected byfiltration with water. The crystals were washed with water and dried togive 6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid(8.1 g, 87%) as crystals.

Melting point 233–235° C. ¹H-NMR(CDCl₃) δ: 0.92 (6H, d, J=6.6 Hz), 2.21(1H, m), 3.99 (2H, d, J=7.6 Hz), 7.32–7.38 (3H, m), 7.42–7.47 (3H, m),7.60 (1H, dd, J=8.4, 2.0 Hz), 8.26 (1H, d, J=8.4 Hz).

(4) 6-Bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-3-carboxylic acid(12.3 g, 30.7 mmol) was dissolved in tetrahydrofuran (100 ml), andoxalyl chloride (3.2 mL, 36.8 mmol) and N,N-dimethylformamide (5 drops)were added thereto. The mixture was stirred at room temperature for 1 h.The reaction mixture was concentrated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (50 mL). The obtained solutionwas added dropwise to a suspension of sodium tetrahydroborate (4.0 g,107 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. The obtained mixturewas stirred at 0° C. for 1 h. The reaction mixture was poured into 1Nhydrochloric acid and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was recrystallized fromdiethyl ether-n-hexane to give6-bromo-3-hydroxymethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (10.7g, 90%) as crystals.

Melting point 176–177° C. ¹H-NMR(CDCl₃) δ: 97 (6H, d, J=6.6 Hz), 2.22(1H, m), 2.35 (1H, t, J=5.8 Hz), 4.21 (2H, d, J=7.6 Hz), 4.44 (2H, d,J=5.8 Hz), 7.10 (1H, d, J=1.8 Hz), 7.30–7.35 (2H, m), 7.47 (1H, dd,J=8.4, 1.8 Hz), 7.50–7.56 (3H, m), 8.20 (1H, d, J=8.4 Hz).

(5) To a solution of6-bromo-3-hydroxymethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (8.7 g,22.5 mmol) and pyridine (5 drops) in tetrahydrofuran (30 mL) and toluene(30 mL) was added thionyl chloride (3.4 mL, 47.3 mmol). The obtainedmixture was stirred at room temperature for 3 h. The reaction mixturewas concentrated, poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give6-bromo-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (8.2 g,90%) as crystals.

Melting point 145–146° C. ¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 2.22(1H, m), 4.17 (2H, d, J=7.6 Hz), 4.37 (2H, s), 7.14 (1H, d, J=1.8 Hz),7.31–7.37 (2H, m), 7.49–7.55 (3H, m), 7.59 (1H, dd, J=8.4, 1.8 Hz), 8.34(1H, d, J=8.4 Hz).

(7) A solution of6-bromo-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (10 g,24.7 mmol) in tetrahydrofuran (20 mL) and a solution of 2M ammonia inethanol (200 mL) were sealed in a stainless tube and stirred at 140° C.for 5 h. The reaction mixture was cooled and concentrated. The residuewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was crystallized fromdiethyl ether and the precipitated crystals were collected by filtrationto give 3-aminomethyl-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(5.6 g, 53%) as crystals.

Melting point 129–130° C. ¹H NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.33(2H, br), 2.12–2.38 (1H, m), 3.65 (2H, s), 4.20 (2H, d, J=7.8 Hz), 7.08(1H, d, J=1.6 Hz), 7.21–7.35 (2H, m), 7.42–7.60 (4H, m), 8.32 (1H, d,J=9.0 Hz). Elemental analysis for C₂₀H₂₁BrN₂O Calculated: C, 62.35; H,5.49; N, 7.27. Found: C, 62.36; H, 5.64; N, 7.44.

Example 107 Methyl3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylatehydrochloride

(1) To a solution of3-aminomethyl-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 106 (7))(5.6 g, 14.5 mmol) and 4-dimethylaminopyridine (20 mg) intetrahydrofuran (50 mL) was added di-t-butyl dicarbonate (6.3 g, 2.9mmol). The obtained mixture was stirred at room temperature for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wascrystallized from diethyl ether to give3-tert-butoxycarbonylaminomethyl-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(6.6 g, 94%) as crystals.

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.23 (1H, m),4.06 (2H, d, J=7.8 Hz), 4.19 (2H, d, J=5.4 Hz), 4.50 (1H, bs), 7.08 (1H,d, J=2.0 Hz), 7.21–7.25 (2H, m), 7.48–7.56 (4H, m), 8.30 (1H, d, J=8.8Hz).

(2) A mixture of3-tert-butoxycarbonylaminomethyl-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(3.0 g, 6.2 mmol), 1,3-bis(diphenylphosphino)propane (0.45 g, 1.1 mol)and triethylamine (0.69 g, 6.8 mmol) in dimethyl sulfoxide (30 ml) andmethanol (15 ml) was stirred under a carbon monoxide atmosphere at roomtemperature for 30 min. Palladium acetate (0.25 g, 1.1 mmol) was addedto the resulting mixture and the mixture was stirred under a carbonmonoxide atmosphere with heating at 80° C. for 15 h. The reactionmixture was poured into water and extracted with ethyl acetate. Afterwashing the extract with water, the extract was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give methyl3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylate(1.92 g, 83.5%) as crystals.

Melting point 205–206° C. Elemental analysis for C₂₇H₃₂N₂O₅ Calculated:C, 69.81; H, 6.94; N, 6.03. Found: C, 69.71; H, 6.80; N, 6.13.¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.26 (1H, m),3.85 (3H, s), 4.09 (2H, d, J=7.6 Hz), 4.22 (2H, d, J=5.6 Hz), 4.47 (1H,bs), 7.23–7.28 (2H, m), 7.49–7.56 (3H, m), 7.66 (1H, d, J=1.0 Hz), 8.05(1H, dd, J=1.7, 8.0 Hz), 8.52 (1H, d, J=8.0 Hz).

(3) To a solution of methyl3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylate(0.2 g, 0.43 mmol) in tetrahydrofuran (10 mL) was added a solution of10% hydrogen chloride in methanol (20 mL). The obtained solution wasstirred at room temperature for 15 h. The reaction mixture wasconcentrated under reduced pressure and the residue was crystallizedfrom diethyl ether to give methyl3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylatehydrochloride (0.17 g, 99%) as crystals.

Elemental analysis for C₂₂H₂₄N₂O₃ HCl ¼H₂O Calculated: C, 65.18; H,6.34; N, 6.91. Found: C, 65.08; H, 6.29; N, 6.86. ¹H-NMR(DMSO-d₆) δ:0.93 (6H, d, J=6.6 Hz), 2.12 (1H, m), 3.80 (3H, s), 3.89 (2H, s), 4.10(2H, d, J=6.6 Hz), 7.42–7.46 (2H, m), 7.54 (1H, d, J=1.6 Hz), 7.54–7.62(3H, m), 8.07 (1H, dd, J=8.4 Hz), 8.47 (1H, d, J=8.4 Hz), 8.58 (3H, s).

Example 1083-Aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylic acidhydrochloride

(1) To a solution of methyl3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylate(synthesized according to the method similar to that in Example 107 (2))(0.28 g, 0.6 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) wasadded 1N sodium hydroxide (5 ml). The obtained mixture was stirred atroom temperature for 2 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-diethyl ether to give3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylicacid (1.54 g, 98.7%) as crystals.

Elemental analysis for C₂₆H₃₀N₂O₅ Calculated: C, 69.31; H, 6.71; N,6.22. Found: C, 69.17; H, 6.59; N, 6.27. ¹H-NMR(CDCl₃) δ: 0.96 (6H, d,J=6.6 Hz), 1.07 (3H, t, J=7.4 Hz), 1.49 (9H, s), 1.50–1.72 (2H, m),1.84–1.98 (2H, m), 2.14–2.21 (1H, m), 3.90 (2H, t, J=6.4 Hz), 4.00 (2H,d, J=6.8 Hz), 4.55 (2H, d, J=5.0 Hz), 5.37 (1H, bs), 8.08–8.13 (1H, m),8.35–8.46 (2H, m).

(2) To a solution of3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylicacid (0.15 g, 0.33 mmol) in tetrahydrofuran (6 mL) was added a solutionof 4N hydrogen chloride in dioxane (10 mL). The obtained solution wasstirred at room-temperature for 15 h. The reaction mixture wasconcentrated under reduced pressure, and the residue was crystallizedfrom diethyl ether to give3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylic acidhydrochloride (0.09 g, 69%) as crystals.

¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.01 (3H, t, J=7.4 Hz),1.50–1.69 (2H, m), 1.80–1.93 (2H, m), 1.99–2.12 (1H, m), 3.97 (2H, t,J=6.4 Hz), 3.99 (2H, d, J=7.6 Hz), 4.21 (2H, s), 8.09 (1H, dd, J=1.4,8.4 Hz), 8.34 (1H, d, J=1.4 Hz), 8.38 (1H, d, J=8.4 Hz), 8.69 (3H, bs).

Example 1093-Aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamidehydrochloride]

(1) A solution of3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylicacid (synthesized according to the method similar to that in Example 108(1)) (0.6 g, 1.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.5 g, 2.6 mmol) and 1-hydroxybenzotriazole ammonium salt(0.4 g, 2.6 mmol) in N,N-dimethylformamide (3 ml) was stirred at roomtemperature for 3 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed successively withsaturated aqueous sodium hydrogencarbonate solution and brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was crystallized from diethyl ether-n-hexane togive3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamide(0.5 g, 86%) as crystals.

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.24 (1H, m),4.08 (2H, d, J=7.2 Hz), 4.20 (2H, d, J=5.4 Hz), 4.68 (1H, bs), 5.73 (1H,bs), 6.08 (1H, bs), 7.24–7.29 (2H, m), 7.38 (1H, d, J=2.0 Hz), 7.47–7.56(3H, m), 7.74 (1H, dd, J=8.8, 2.0 Hz), 8.45 (1H, d, J=8.8 Hz).

(2) To a solution of3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamide(0.15 g, 0.33 mmol) in tetrahydrofuran (6 mL) was added a solution of 4Nhydrogen chloride in dioxane (10 mL). The obtained solution was stirredat room temperature for 6 h. The reaction mixture was concentrated underreduced pressure, and the residue was crystallized from diethyl ether togive3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride (0.11 g, 85%) as crystals.

Melting point 240–242° C. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz),2.11 (1H, m), 3.87 (2H, d, J=5.6 Hz), 4.10 (2H, d, J=7.2 Hz), 7.39 (1H,d, 1.4 Hz), 7.40–7.43 (2H, m), 7.56–7.62 (4H, m), 8.00 (1H, dd, J=8.4,1.4 Hz), 8.16 (1H, s), 8.37 (1H, d, J=8.4 Hz), 8.61 (3H, bs).

Example-1103-Aminomethyl-6-benzyloxycarbonylamino-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) A solution of3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxyacid (synthesized according to the method similar to that in Example 108(1)) (0.5 g, 1.1 mmol), diphenylphosphoryl azide (0.28 ml, 1.3 mmol) andtriethylamine (0.18 ml, 1.3 mmol) in N,N-dimethylformamide (5 ml) wasstirred at room temperature for 2 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in toluene (20 ml) and themixture was stirred with heating at 100° C. for 2 h. To the obtainedmixture was added benzyl alcohol (0.14 ml, 1.3 mmol) and the mixture wasstirred with heating at 100° C. for 1 h. The reaction mixture wascooled, poured into water and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was crystallized fromdiisopropyl ether to give6-benzyloxycarbonylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(0.47 g, 77%) as crystals.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.23 (1H, m),4.05 (2H, d, J=7.6 Hz), 4.18 (2H, d, J=5.2 Hz), 4.47 (1H, bs), 5.13 (2H,s), 6.75 (1H, d, J=1.8 Hz), 6.76 (1H, s), 7.21–7.26 (2H, m), 7.34–7.75(5H, m), 7.45–7.56 (3H, m), 7.65 (1H, dd, J=8.8, 1.8 Hz), 8.41 (1H, d,J=8.8 Hz).

(2) To a solution of6-benzyloxycarbonylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(0.07 g, 0.13 mmol) in tetrahydrofuran (2 mL) was added a solution, of4N hydrogen chloride in ethyl acetate (10 mL). The obtained solution wasstirred at room temperature for 5 h. The reaction mixture wasconcentrated under reduced pressure and the residue was crystallizedfrom diethyl ether to give3-aminomethyl-6-benzyloxycarbonylamino-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride (0.05 g, 81%) as crystals.

¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 2.08 (1H, m), 3.84 (2H, s),4.03 (2H, d, J=7.4 Hz), 5.08 (2H, s), 7.22 (1H, d, J=1.8 Hz), 7.35–7.37(7H, s), 7.54–7.58 (2H, m), 7.64 (1H, dd, J=8.8, 1.8 Hz), 8.24 (1H, d,J=8.8 Hz), 8.44 (3H, s), 10.16 (1H, s).

Example 1116-Amino-3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinonedihydrochloride

(1) To a mixed solution of6-benzyloxycarbonylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 110 (1))(0.45 g, 0.81 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) wasadded 5% palladium-carbon (0.1 g). The obtained mixture washydrogenated, at ambient temperature and atmospheric pressure. Thecatalyst was filtered off and the filtrate was concentrated underreduced pressure. The precipitated crystals were collected by filtrationto give6-amino-3-tert-butoxycarbonylaminomethyl-2isobutyl-4-phenyl-1(2H)-isoquinolinone(0.31 g, 87.0%) as crystals.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.8, Hz), 1.42 (9H, s), 2.22 (1H, m),3.94 (2H, bs), 4.02 (2H, d, J=7.4 Hz), 4.15 (2H, d, J=5.4 Hz), 4.40 (1H,bs), 6.12 (1H, d, J=2.2 Hz), 6.78 (1H, dd, J=8.8, 2, 2 Hz), 7.21–7.26(2H, m), 7.44–7.53 (3H, m), 8.27 (1H, d, J=8.8 Hz).

(2) 6-Amino-3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinonedihydrochloride was synthesized from6-amino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinoneaccording to the method similar to that in Example 110 (2).

¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 2.05 (1H, m), 3.76 (2H, bs),3.99 (2H, d, J=6.6 Hz), 5.44 (3H, bs), 6.00 (1H, d, J=2.0 Hz), 6.84 (1H,dd, t, J=8.8, 2.0 Hz), 7.34–7.38 (2H, m), 7.50–7.59 (3H, m), 8.03 (1H,d, J=8.8 Hz), 8.48 (3H, bs).

Example 1126-Acetylamino-3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) A mixture of6-amino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 111 (1))(0.1 g, 0.24 mmol), acetyl chloride (38 mg, 0.48 mmol), sodiumhydrogencarbonate (81 mg, 0.96 mmol), water (0.5 ml) and ethyl acetate(5 ml) was stirred at room temperature for 2 h. The reaction mixture wasextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was crystallized from diisopropyl ether to give6-acetylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(80 mg, 73%) as crystals.

¹H-NMR(CDCl₃) δ: 0.87 (6H, d, J=7.0 Hz), 1.42 (9H, s), 2.10 (3H, s),2.23 (1H, m), 4.05 (2H, d, J=7.4 Hz), 4.19 (2H, d, J=5.6 Hz), 4.60 (1H,bs), 6.95 (1H, s), 7.24–7.28 (2H, m), 7.37 (1H, s), 7.47–7.55 (3H, m),7.69 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8 Hz).

(2) 6-Acetylamino-3aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride was synthesized from6-acetylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinoneaccording to the method-similar to that in Example 110 (2).

¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz) 1.98 (3H, s), 2.08 (1H, m),3.84 (2H, s), 4.03 (2H, d, J=7.0 Hz), 7.19 (1H, d, J=1.8 Hz), 7.35–7.39(2H, m), 7.49–7.58 (3H, m), 7.86 (1H, dd, J=8.8, 1.8 Hz), 8.25 (1H, d,J=8.8 Hz), 8.45 (3H, bs), 10.28 (1H, s).

The compounds of the following Examples 113 to 130 were synthesizedaccording to the method similar to that in Example 106.

Example 1133-(Aminomethyl)-6-chloro-2-ethyl-4-phenyl-1(2H)-isoquinolinone

Melting point 126–127° C. ¹H-NMR (CDCl₃) δ: 1.39 (2H, br), 1.42 (3H, t,J=7.0 Hz), 3.64 (2H, s), 4.43 (2H, q, J=7.0 Hz), 6.91 (1H, d, J=2.2 Hz),7.23–7.31 (2H, m), 7.38 (1H, dd, J=2.2 and 8.4 Hz), 7.45–7.57 (3H, m),8.41 (1H, d, J=8.4 Hz). Elemental analysis for C₁₈H₁₇ClN₂O.0.125H₂OCalculated: C, 68.62; H, 5.51; N, 8.89. Found: C, 68.61; H, 5.40; N,8.84.

Example 1143-(Aminomethyl)-6-chloro-4-phenyl-2-propyl-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 1.04 (3H, t, J=7.4 Hz), 1.17 (2H, br), 1.71–1.93 (2H,m), 3.63 (2H, s), 4.28 (2H, t, J=7.6 Hz), 6.90 (1H, d, J=2.2 Hz),7.21–7.32 (2H, m), 7.37 (1H, dd, J=2.2 and 8.4 Hz), 7.41–7.58 (3H, m),8.40 (1H, d, J=8.4 Hz). Elemental analysis for C₁₉H₁₉ClN₂O Calculated:C, 69.83; H, 5.86; N, 8.57. Found: C, 69.97; H, 5.90; N, 8.49.

Example 1153-(Aminomethyl)-2-butyl-6-chloro-4-phenyl-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 1.00 (3H, t, J=7.4 Hz), 1.23 (2H, br), 1.38–1.60 (2H,m), 1.68–1.84 (2H, m), 3.63 (2H, s), 4.33 (2H, t, J=7.6 Hz), 6.90 (1H,d, J=2.0 Hz), 7.22–7.31 (2H, m), 7.38 (1H, dd, J=2.0 and 8.8 Hz),7.45–7.58 (3H, m), 8.41 (1H, d, J=8.8 Hz). Elemental analysis forC₂₀H₂₁ClN₂O Calculated: C, 70.48; H, 6.21; N, 8.22. Found: C, 70.27; H,6.18; N, 8.09.

Example 1163-(Aminomethyl)-6-bromo-2-methyl-4-phenyl-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 1.30 (2H, br), 3.66 (2H, s), 3.84 (3H, s), 7.10 (1H,d, J=2.0 Hz), 7.20–7.32 (2H, m), 7.45–7.59 (4H, m), 8.33 (1H, d, J=8.8Hz). Elemental analysis for C₁₇H₁₅BrN₂O Calculated: C, 59.49; H, 4.41;N, 8.16. Found: C, 59.61; H, 4.65; N, 7.78.

Example 1173-(Aminomethyl)-6-chloro-2-pentyl-4-phenyl-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.4 Hz), 1.20–1.53 (6H, m), 1.70–1.90(2H, m), 3.63 (2H, s), 4.31 (2H, t, J=8.0 Hz), 6.90 (1H, d, J=2.2 Hz),7.22–7.31 (2H, m), 7.37 (1H, dd, J=2.2 and 8.4 Hz), 7.45–7.58 (3H, m),8.40 (1H, d, J=8.4 Hz). Elemental analysis for C₂₁H₂₃ClN₂O Calculated:C, 71.07; H, 6.53; N, 7.89. Found: C, 70.82; H, 6.34; N, 7.72.

Example 1183-(Aminomethyl)-6-chloro-2-isobutyl-4-phenyl-1(2H)-isoquinolinone

Melting point 123–124° C. ¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.18(2H, br), 2.12–2.38 (1H, m), 3.66 (2H, s), 4.20 (2H, d, J=7.4 Hz), 6.90(1H, d, J=1.6 Hz), 7.21–7.31 (2H, m), 7.37 (1H, dd, J=1.6 and 8.4 Hz),7.45–7.58 (3H, m), 8.40 (1H, d, J=8.4 Hz). Elemental analysis forC₂₀H₂₁ClN₂O Calculated: C, 70.48; H, 6.21; N, 8.22. Found: C, 70.35; H,6.07; N, 8.10.

Example 1193-(Aminomethyl)-6-chloro-2-(cyclohexylmethyl)-4-phenyl-1(2H)-isoquinolinone

¹H-NNR (CDCl₃) δ: 1.00–1.47 (8H, m), 1.56–2.00 (5H, m), 3.66 (2H, s),4.21 (2H, d, J=6.8 Hz), 6.90 (1H, d, J=2.0 Hz), 7.22–7.32 (2H, m), 7.37(1H, dd, J=2.0 and 8.8 Hz), 7.47–7.58 (3H, m), 8.40 (1H, d, J=8.8 Hz).Elemental analysis for C₂₃H₂₅ClN₂O Calculated: C, 72.52; H, 6.62; N,7.35. Found: C, 72.34; H, 6.76; N, 7.21.

Example 1203-(Aminomethyl)-6,7-dichloro-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinonehydrochloride

¹H-NMR (CDCl₃, free base) δ: 0.99 (6H, d, J=6.8 Hz), 1.36 (2H, br),2.10–2.35 (1H, m), 3.65 (2H, s), 4.20 (2H, d, J=7.6 Hz), 6.99 (1H, s),7.24 (4H, d, J=7.4 Hz), 8.53 (1H, s). Elemental analysis forC₂₀H₁₉Cl₂N₂OF.HCl.H₂O Calculated: C, 53.65; H, 4.95; N, 6.26. Found: C,53.69; H, 4.84; N, 5.96.

Example 1213-(Aminomethyl)-6,7-dichloro-2-isobutyl-4-phenyl-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.13 (2H, br), 2.10–2.36 (1H,m), 3.65 (2H, s), 4.20 (2H, d, J=7.4 Hz), 7.02 (1H, s), 7.20–7.32 (2H,m), 7.45–7.59 (3H, m), 8.54 (1H, s). Elemental analysis for C₂₀H₂₀Cl₂N₂OCalculated: C, 64.01; H, 5.37; N, 7.46. Found: C, 63.71; H, 5.39; N,7.23.

Example 1223-(Aminomethyl)-6-chloro-2-neopentyl-4-phenyl-1(2H)-isoquinolinone

Melting point 173–174° C. ¹H-NMR (CDCl₃) δ: 1.02 (9H, s), 1.23 (2H, br),3.71 (2H, s), 4.30 (2H, br), 6.90 (1H, d, J=2.2 Hz), 7.20–7.30 (2H, m),7.37 (1H, dd, J=2.2 and 8.4 Hz), 7.42–7.68 (3H, m), 8.39 (1H, d, J=8.4Hz). Elemental analysis for C₂₁H₂₃ClN₂O Calculated: C, 71.07; H, 6.53;N, 7.89. Found: C, 70.89; H, 6.54; N, 7.61.

Example 123 3-(Aminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone

Melting point 129–130° C. ¹H-NMR (CDCl₃) δ: 1.01 (6H, d, J=7.0 Hz), 1.23(2H, br), 2.17–2.40 (1H, m), 3.68 (2H, s), 4.22 (2H, d, J=7.8 Hz),6.90–7.00 (1H, m), 7.23–7.34 (2H, m), 7.38–7.57 (5H, m), 8.44–8.52 (1H,m). Elemental analysis for C₂₀H₂₂N₂O Calculated: C, 78.40; H, 7.24; N,9.14. Found: C, 78.30; H, 7.50; N, 9.06.

Example 1243-(Aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone

Melting point 119–120° C. ¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.15(1H, br), 1.61 (1H, br), 2.14–2.39 (1H, m), 3.67 (2H, s), 4.21 (2H, d,J=7.8 Hz), 6.88–6.97 (1H, m), 7.20–7.29 (2H, m), 7.40–7.56 (4H, m),8.43–8.52 (1H, m). Elemental analysis for C₂₀H₂₁ClN₂O Calculated: C,70.48; H, 6.21; N, 8.22. Found: C, 70.36; H, 6.40; N, 8.19.

Example 1253-(Aminomethyl)-4-(4-methylphenyl)-2-isobutyl-1(2H)-isoquinolinonehydrochloride

Melting point 178–180° C. (dec.) ¹H-NMR (CDCl₃, free base) δ: 1.00 (6H,d, J=6.6 Hz), 1.48 (2H, br), 2.18–2.37 (1H, m), 2.46 (3H, s), 3.69 (2H,s), 4.22 (2H, d, J=7.8 Hz), 6.95–7.04 (1H, m), 7.17 (2H, d, J=8.0 Hz),7.31 (2H, d, J=7.0 Hz), 7.37–7.53 (2H, m), 8.43–8.53 (1H, m). Elementalanalysis for C₂₁H₂₄N₂O.HCl.0.5H₂O Calculated: C, 68.93; H, 7.16; N,7.66. Found: C, 69.25; H, 7.11; N, 7.30.

Example 1263-(Aminomethyl)-6-fluoro-2-isobutyl-4-phenyl-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.12 (2H, br), 2.15–2.38 (1H,m), 3.67 (2H, s), 4.20 (2H, d, J=7.4 Hz), 6.56 (1H, dd, J=2.6 and 10.6Hz), 7.13 (1H, dt, J=2.6 and 8.8 Hz), 7.23–7.33 (2H, m), 7.41–7.57 (3H,m), 8.48 (1H, dd, J=5.8 and 8.8 Hz). Elemental analysis forC₂₀H₂₁FN₂O.0.25H₂O Calculated: C, 73.04; H, 6.59; N, 8.52. Found: C,73.32; H, 6.72; N, 8.43.

Example 1273-(Aminomethyl)-2-isobutyl-6-methoxy-4-phenyl-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.26 (2H, br), 2.15–2.38 (1H,m), 3.65 (2H, s), 3.67 (3H, s), 4.18 (2H, d, J=7.2 Hz), 6.30 (1H, d,J=2.4 Hz), 7.02 (1H, dd, J=2.4 and 8.8 Hz), 7.23–7.34 (2H, m), 7.39–7.57(3H, m), 8.41 (1H, d, J=8.8 Hz). Elemental analysis for C₂₁H₂₄N₂O₂Calculated: C, 74.97; H, 7.19; N, 8.33. Found: C, 74.73; H, 7.40; N,8.32.

Example 1283-(Aminomethyl)-6-ethoxy-2-isobutyl-4-phenyl-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.21 (2H, br), 1.33 (3H, t,J=7.0 Hz), 2.13–2.38 (1H, m), 3.65 (2H, s), 3.88 (2H, q, J=7.0 Hz), 4.18(2H, d, J=7.4 Hz), 6.29 (1H, d, J=2.6 Hz), 7.01 (1H, dd, J=2.6 and 8.8Hz), 7.22–7.32 (2H, m), 7.41–7.55 (3H, m), 8.39 (1H, d, J=8.8 Hz).Elemental analysis for C₂₂H₂₆N₂O₂ Calculated: C, 75.40; H, 7.48; N,7.99. Found: C, 75.43; H, 7.69; N, 8.17.

Example 1293-(Aminomethyl)-2-isobutyl-4-phenyl-6-propoxy-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.4 Hz), 0.99 (6H, d, J=7.0 Hz), 1.32(2H, br), 1.61–1.82 (2H, m), 2.13–2.38 (1H, m), 3.64 (2H, s), 3.77 (2H,t, J=6.6 Hz), 4.18 (2H, d, J=7.4 Hz), 6.28 (1H, d, J=2.6 Hz), 7.01 (1H,dd, J=2.6 and 9.2 Hz), 7.22–7.31 (2H, m), 7.42–7.56 (3H, m), 8.39 (1H,d, J=9.2 Hz). Elemental analysis for C₂₃H₂₈N₂O₂ Calculated: C, 75.79; H,7.74; N, 7.69. Found: C, 75.81; H, 7.45; N, 7.56.

Example 1303-(Aminomethyl)-2-isobutyl-6,7-dimethoxy-4-phenyl-1(2H)-isoquinolinone

¹H-NMR (CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.34 (2H, br), 2.15–2.40 (1H,m), 3.66 (5H, s), 4.01 (3H, s), 4.21 (2H, d, J=7.4 Hz), 6.28 (1H, s),7.25–7.35 (2H, m), 7.40–7.57 (3H, m), 7.87 (1H, s). Elemental analysisfor C₂₂H₂₆N₂O₃.0.5H₂O Calculated: C, 70.38; H, 7.25; N, 7.46. Found: C,70.56; H, 7.36; N, 7.39.

Example 1313-(Aminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carbonitrilehydrochloride

(1) A solution of3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamide(synthesized according to the method similar to that in Example 109 (1))(0.3 g, 0.67 mmol) and cyanuric chloride (0.37 g, 2 mmol) inN,N-dimethylformamide (3 mL) was stirred at 0° C. for 1 h. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed successively with water, 10% aqueous citric acidsolution, saturated aqueous sodium hydrogencarbonate solution and brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give a amorphous solid oftert-butyl(6-cyano-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.28 g, 97%).

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.24 (1H, m),4.09 (2H, d, J=7.0 Hz), 4.23 (2H, d, J=5.4 Hz), 4.43 (1H, bs), 7.21–7.29(3H, m), 7.51–7.59 (3H, m), 7.65 (1H, dd, J=1.4, 8.0 Hz), 8.55 (1H, d,J=8.0 Hz).

(2)3-(Aminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carbonitrilehydrochloride was synthesized fromtert-butyl(6-cyano-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamatein the same manner as in Example 1 (7).

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.11 (1H, m), 3.89 (2H, s),4.11 (2H, d, J=7.4 Hz), 7.22 (1H, d, J=1.6 Hz), 7.42–7.46 (2H, m),7.58–7.61 (3H, m), 7.97 (1H, dd, J=1.6, 8.4 Hz), 8.48 (1H, d, J=8.4 Hz),8.67 (3H, bs).

Example 1323-(Aminomethyl)-4-phenyl-6-(1-pyrrolidinylcarbonyl)-2-isobutyl-1(2H)-isoquinolinonehydrochloride

(1) A mixture of3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylicacid (synthesized according to the method similar to that in Example 108(1)) (100 mg, 0.22 mmol), hydrochloric acid1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(63 mg, 0.33mmol), 1-hydroxy-7-azabenzotriazole (30 mg, 0.22 mmol), pyrrolidine (31mg, 0.44 mmol) and N,N-dimethylformamide (3 mL) was stirred at roomtemperature for 3 h. The reaction mixture was poured into 10% aqueouscitric acid solution and extracted with ethyl acetate. The extract wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give3-(tert-butoxycarbonylaminomethyl)-2-isobutyl-4-phenyl-6-(1-pyrrolidinylcarbonyl)-1(2H)-isoquinolinone(70 mg, 64%) as an amorphous solid.

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.43 (9H, s), 1.79–1.99 (4H,m), 2.25 (1H, m), 3.21 (2H, t, J=6.2 Hz), 3.57 (2H, t, J=6.8 Hz), 4.09(2H, d, J=7.6 Hz), 4.21 (2H, d, J=6.0 Hz), 4.44 (1H, bs), 7.08 (1H, d,J=1.6 Hz), 7.21–7.27 (2H, m), 7.45–7.51 (3H, m), 7.56 (1H, dd, J=8.4,1.6 Hz), 8.50 (1H, d, J=8.4 Hz).

(2)3-(Aminomethyl)-2-isobutyl-4-phenyl-6-(1-pyrrolidinylcarbonyl)-1(2H)-isoquinolinonehydrochloride was synthesized from3-(tert-butoxycarbonylaminomethyl)-2-isobutyl-4-phenyl-6-(1-pyrrolidinylcarbonyl)-1(2H)-isoquinolinonein the same manner as in Example 1 (7).

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 1.70–1.90 (4H, m), 2.11 (1H,m), 3.20 (2H, t, J=6.4 Hz), 3.90 (2H, t, J=6.2 Hz), 3.88 (2H, s), 4.09(2H, d, J=7.4 Hz), 6.96 (1H, d, J=1.6 Hz), 7.39–7.44 (2H, m), 7.56–7.164(3H, m), 7.69 (1H, dd, J=8.4, 1.6 Hz), 8.37 (1H, d, J=8.4 Hz), 8.55 (3H,bs).

The compounds of the following Examples 133 to 141 were synthesizedaccording to the method similar to that in Example 132.

Example 1333-Aminomethyl-N-benzyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.11 (1H, m), 3.88 (2H, s),4.09 (2H, d, J=6.6 Hz), 4.36 (2H d, J=6.0 Hz), 7.22–7.34 (5H, m),7.40–7.45 (3H, m), 7.57–7.60 (3H, m), 8.04 (1H, d, J=8.4 Hz), 8.41 (1H,d. J=8.4 Hz), 8.52 (3H, bs), 9.28 (1H, t, J=6.0 Hz).

Example 1343-Aminomethyl-2-isobutyl-N-methyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.11 (1H, m), 2.72 (3H, d,J=4.8 Hz), 3.87 (2H, s), 4.09 (2H, d, J=6.8 Hz), 7.39–7.43 (3H, m),7.54–7.60 (3H, m), 7.95 (1H, dd, J=8.6, 1.6 Hz), 8.39 (1H, d, J=8.6 Hz),8.60 (3H, bs), 8.64 (1H, t, J=4.8 Hz).

Example 1353-Aminomethyl-N-cyclopropyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

¹H-NMR(DMSO-d₆) δ: 0.49–0.59 (2H, m), 0.62–0.71 (2H, m), 0.92 (6H, d,J=6.6 Hz), 2.11 (1H, m), 2.73 (1H, m), 3.88 (2H, s), 4.08 (2H, d, J=7.0Hz), 7.39 (1H, d, J=1.4 Hz), 7.40–7.43 (2H, m), 7.58–7.61 (3H, m), 7.94(1H, dd, J=8.4, 1.4 Hz), 8.37 (1H, d, J=8.4 Hz), 8.46 (3H, bs), 8.66(1H, t, J=4.0 Hz).

Example 1363-Aminomethyl-2-isobutyl-4-phenyl-N-propyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

¹H-NMR(DMSO-d₆) δ: 0.83 (3H, t, J=7.4 Hz), 0.92 (6H, d, J=6.6 Hz),1.40–1.60 (2H, m), 2.11 (1H, m), 3.15 (2H, m), 3.88 (2H, s), 4.08 (2H,d, J=7.0 Hz), 7.39 (1H, d, J=1.6 Hz), 7.39–7.43 (2H, m), 7.57–7.60 (3H,m), 7.97 (1H, dd, J=8.4, 1.6 Hz), 8.39 (1H, d, J=8.4 Hz), 8.45 (3H, bs),8.66 (1H, t, J=4.8 Hz).

Example 1373-Aminomethyl-N-ethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 1.07 (3H, t, J=7.0), 2.11(1H, m), 3.15–3.29 (2H, m), 3.87 (2H, s), 4.08 (2H, d, J=7.0 Hz),7.38–7.43 (3H, m), 7.55–7.63 (3H, m), 7.97 (1H, dd, J=8.4, 1.8 Hz), 8.38(1H, d, J=8.4 Hz), 8.45 (3H, bs), 8.68 (1H, t, J=5.0 Hz).

Example 1383-Aminomethyl-N,N-dimethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.11 (1H, m), 2.78 (3H, s),2.91 (3H, s), 3.88 (2H, s), 4.08 (2H, d, J=7.4 Hz), 6.84 (1H, d, J=1.0Hz), 7.39–7.43 (2H, m), 7.54–7.61 (4H, m), 8.37 (1H, d, J=8.6 Hz), 8.50(3H, bs).

Example 139 EthylN-[(3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-yl)carbony]glycinatehydrochloride

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 117 (3H, t, J=7.2 Hz), 2.11(1H, m), 3.88 (2H, s), 3.94 (2H, d, J=5.6 Hz), 4.08 (2H, g, J=7.2 Hz),4.08 (2H, d, J=7.0 Hz), 7.39–7.43 (3H, m), 7.57–7.60 (3H, m), 8.00 (1H,dd, J=8.4, 1.6 Hz), 8.43 (1H, d, J=8.4 Hz), 8.43 (3H, bs), 9.15 (1H, t,J=5.6 Hz).

Example 1403-(Aminomethyl)-6-[(4-hydroxypiperidin-1-yl)carbonyl]-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 1.20–1.80 (6H, m), 2.11 (1H,m), 2.90–3.30 (2H, m), 3.67 (1H, m), 3.89 (2H, s), 4.07 (2H, d, J=6.4Hz), 4.80 (1H, bs), 6.83 (1H, m), 7.40–7.43 (2H, m), 7.54–7.61 (4H, m),8.38 (1H, d, J=8.4 Hz), 8.46 (3H, bs).

Example 1413-Aminomethyl-N-(2,2,2-trifluoroethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.12 (1H, m), 3.89 (2H, s),4.00–4.10 (4H, m), 7.39–7.44 (3H, m), 7.57–7.61 (3H, m), 8.02 (1H, dd,J=8.6, 1.4 Hz), 8.44 (1H, d, J=8.4 Hz), 8.46 (3H, bs), 9.31 (1H, t,J=6.3 Hz).

Example 1423-Aminomethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

(1) To a solution of 4-bromophthalic anhydride (50 g, 220 mmol) influorobenzene (300 mL) was added aluminum chloride (60 g, 450 mmol) bysmall portions under ice-cooling. The-obtained mixture was stirred atroom temperature for 15 h. The reaction mixture was poured into icewater and extracted with ethyl acetate. The extract was washed with 1Nhydrochloric acid and brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was crystallized fromethyl acetate-diisopropyl ether and the precipitated crystals werecollected by filtration. The crystals were recrystallized from ethylacetate to give a solid of a mixture (9:1)(7 g, 10%) of2-(4-fluorobenzoyl)-4-bromobenzoic acid and2-(4-fluorobenzoyl)-5-bromobenzoic acid.(2-(4-fluorobenzoyl)-4-bromobenzoic acid: ¹H-NMR(CDCl₃) δ: 7.06–7.17(2H, m), 7.50 (1H, d, J=2.0 Hz), 7.69–7.79 (3H, m), 7.95 (1H, d, J=8.4Hz).

(2) A solid of 6-bromo-4-(4-fluorophenyl)-1H-isochromene-3-carboxylicacid (5.5 g, 69%) was obtained from 2-(4-fluorobenzoyl)-4-bromobenzoicacid (7 g, 22 mmol) in the same manner as in Example 106 (2).

¹H-NMR(CDCl₃) δ: 7.21–7.27 (5H, m), 7.79 (1H, dd, J=8.4, 1.8 Hz), 8.27(1H, d, J=8.6 Hz).

(3)6-Bromo-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-3-carboxylicacid (5.3 g, 85%) was obtained as crystals from6-bromo-4-(4-fluorophenyl)-1H-isochromene-3-carboxylic acid (5.4 g, 14.9mmol) in the same manner as in Example 106 (3).

¹H-NMR(CDCl₃) δ: 0.94 (6H, d, J=7.0 Hz), 2.28 (1H, m), 4.02 (2H, d,J=7.4 Hz), 7.12–7.25 (3H, m), 7.33–7.41 (2H, m), 7.61 (1H, dd, J=8.4,1.8 Hz), 8.34 (1H, d, J=8.4 Hz).

(4)6-Bromo-4-(4-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(4.9 g, 96%) was obtained as crystals from6-bromo-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-3-carboxylicacid (5.3 g, 12.6 mmol) in the same manner as in Example 106 (4).

Melting point 194–196° C. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=7.0 Hz), 1.94(1H, t, J=6.0 Hz), 2.21 (1H, m), 4.20 (2H, d, J=7.4 Hz), 4.44 (2H, d,J=5.6 Hz), 7.09 (1H, d, J=1.8 Hz), 7.18–7.34 (4H, m), 7.52 (1H, dd,J=8.6, 1.8 Hz), 8.26 (1H, d, J=8.6 Hz).

(5)6-Bromo-3-chloromethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(4.5 g, 90%) was obtained as crystals from6-bromo-4-(4-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(4.8 g, 11.9 mmol) in the same manner as in Example 106 (5).

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=7.0 Hz), 2.21 (1H, m), 4.17 (2H, d,J=7.2 Hz), 4.36 (2H, s), 7.11 (1H, d, J=1.8 Hz), 7.19–7.36 (4H, m), 7.60(1H, dd, J=8.4, 1.8 Hz), 8.34 (1H, d, J=8.4 Hz).

(6)3-(Tert-butoxycarbonylaminomethyl)-6-bromo-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(4.5 g, 86%) was obtained as crystals from6-bromo-3-chloromethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(4.5 g, 10.6 mmol) in the same manner as in Example 106 (6), (7).

¹H NMR (CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.19 (1H, m),4.05 (2H, d, J=7.2 Hz), 4.18 (2H, d, J=5.0 Hz), 4.43 (1H, bs), 7.05 (1H,d, J=1.8 Hz), 7.21–7.24 (4H, m), 7.56 (1H, dd, J=8.6, 1.8 Hz), 8.31 (1H,d, J=8.6 Hz).

(7) Methyl3-(tert-butoxycarbonylaminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxylate(1.4 g, 33%) was obtained as crystals from3-(tert-butoxycarbonylaminomethyl)-6-bromo-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(4.5 g, 8.9 mmol) in the same-manner as in Example 107 (2).

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.24 (1H, m),3.87 (3H, s), 4.08 (2H, d, J=7.4 Hz), 4.21 (2H, d, J=5.0 Hz), 4.45 (1H,bs), 7.22–7.26 (4H, m), 7.62 (1H, d, J=2.0 Hz), 8.05 (1H, dd, J=8.4, 2.0Hz), 8.52 (1H, d, J=8.4 Hz).

(8)3-(tert-Butoxycarbonylaminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxylicacid (1.1 g, 92%) was obtained as a solid from methyl3-(tert-butoxycarbonylaminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxylate(1.2 g, 2.5 mmol) in the same manner as in Example 108 (1).

¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.38 (9H, s), 2.17 (2H, m),3.93 (2H, d, J=7.6 Hz), 3.99 (2H, d, J=4.4 Hz), 7.33 (1H, bs), 7.37–7.48(4H, m), 7.51 (1H, d, J=1.4H), 8.00 (1H, dd, J=8.4, 1.4 Hz), 8.40 (1H,d, J=8.4 Hz).

(9)3-(Tert-butoxycarbonylaminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamide(0.57 g, 95%) was obtained as a solid from3-(tert-butoxycarbonylaminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxylicacid (0.6 g, 1.3 mmol) in the same manner as in Example 109 (1).

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.44 (9H, s), 2.26 (2H, m),4.07 (2H, d, J=6.8 Hz), 4.20 (2H, d, J=4.8 Hz), 4.62 (1H, bs), 5.12 (1H,bs), 6.03 (1H, bs), 7.22–7.26 (4H, m), 7.38 (1H, s), 7.74 (1H, d, J=8.0Hz), 8.44 (1H, bs).

(10) To a solution of3-(tert-butoxycarbonylaminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamide(0.5 g, 1.1 mmol) in tetrahydrofuran (2 mL) was added a solution of 4Nhydrogenchloride in ethyl acetate (10 mL). The obtained solution wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure and the residue was crystallizedfrom diethyl ether to give3-aminomethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride (0.37 g, 85%) as crystals.

Melting point 218–220° C. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz),2.10 (1H, m), 3.86 (2H, d, J=4.6 Hz), 4.08 (2H, d, J=7.4 Hz), 7.36–7.46(5H, m), 7.59 (1H, s), 8.00 (1H, dd, J=8.4, 1.6 Hz), 8.17 (1H, s), 8.37(1H, d, J=8.4 Hz), 8.55 (3H, bs).

Example 143 Methyl3-aminomethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxylatehydrochloride

This compound was synthesized from methyl3-(tert-butoxycarbonylaminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxylatein the same manner as in Example 142(10).

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.11 (1H, m), 3.81 (3H, s),3.88 (2H, s), 4.08 (2H, d, J=7.8 Hz), 7.39–7.52 (5H, m), 8.08 (1H, dd,J=8.4, 1.6 Hz), 8.46 (1H, d, J=8.4 Hz), 8.50 (3H, s).

Example 1443-Aminomethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxylicacid hydrochloride

This compound was synthesized from3-(tert-butoxycarbonylaminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxylicacid in the same manner as in Example 142(10).

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.14 (1H, m), 3.89 (2H, s),4.08 (1H, s, J=7.8 Hz), 7.39–7.52 (5H, m), 8.06 (1H, dd, J=8.4, 1.6 Hz),8.44 (1H, d, J=8.4 Hz), 8.50 (3H, bs).

Example 1453-Aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamide[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide]

To a solution of3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride (2.04 g, 5 mmol) in water (20 mL) was added 1N sodiumhydroxide (10 ml) and the obtained mixture was stirred at roomtemperature for 10 min. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethyl acetateto give3-aminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxamide(0.87 g, 82.9%) as crystals.

Melting point 208° C. Elemental analysis for C₂₁H₂₃N₃O₂. Calculated: C,72.18; H, 6.63; N, 12.03. Found: C, 72.10; H, 6.56; N, 11.88.¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.42 (2H, bs), 2.20–2.34 (1H,m), 3.68 (2H, s), 4.23 (2H, d, J=7.6 Hz), 5.72 (1H, bs), 6.01 (1H, bs),5.89 (1H, bs), 7.26–7.31 (2H, m), 7.20 (1H, d, J=2.2 Hz), 7.46–7.57 (3H,m), 7.79 (1H, dd, J=1.8, 8.4 Hz), 8.54 (1H, d, J=8.4 Hz).

Powder X-ray crystal diffraction data Diffraction angle: 2θ(°)(angstrom) spacing: d value 5.98 14.8 7.88 11.2 8.44 10.5 17.1 5.19

Recrystallization from ethyl acetate in the same manner gave crystals ina:different crystal form.

Powder X-ray crystal diffraction data Diffraction angle: 2θ(°)(angstrom) spacing: d value 7.22 11.4 9.80 9.02 12.1 7.32 13.5 6.53 17.94.94 19.6 4.52 20.6 4.30 21.8 4.08

Example 1463-(Aminomethyl)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamidehydrochloride

(1) A solution of 4-bromophthalic anhydride (22.70 g, 100 mmol) andethyl 2-(cycloproplylmethylamino)acetate (18.87 g, 120 mmol) intetrahydrofuran (150 mL) was stirred at room temperature for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasdissolved in N,N-dimethylformamide (150 mL), and potassium carbonate(14.82 g, 100 mmol) and ethyl iodide (9.6 mL, 120 mmol) were addedthereto. The mixture was stirred at room temperature for 12 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasdissolved in ethanol (150 mL) and 20% sodium ethoxide ethanol solution(68.10 g, 200 mmol) was added thereto. The mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into 1Nhydrochloric acid (300 mL) and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography and the component eluted earlier wasconcentrated to give ethyl7-bromo-2-cyclopropylmethyl-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(11.14 g, 30.4%) as crystals.

Melting point 105–105.5° C. Elemental analysis for C₁₆H₁₆NO₄BrCalculated: C, 52.48; H, 4.40; N, 3.82. Found: C, 52.50; H, 4.31; N,3.80. ¹H-NMR(CDCl₃) δ: 0.32–0.54 (4H, m), 0.97–1.14 (1H, m), 1.47 (3H,t, J=7.2 Hz), 4.34 (2H, d, J=7.0 Hz), 4.45 (2H, d, J=7.2 Hz), 7.85 (1H,dd, J=2.0, 8.6 Hz), 8.02 (1H, d, J=8.6 Hz), 8.59 (1H, d, J=2.6 Hz),11.25 (1H, s).

The component eluted later was concentrated to give ethyl6-bromo-2-cyclopropylmethyl-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(11.02 g, 30.1%) as crystals.

Melting point 64–65° C. Elemental analysis for C₁₆H₁₆NO₄Br Calculated:C, 52.48; H, 4.40; N, 3.82. Found: C, 52.36; H, 4.31; N, 3.87.¹H-NMR(CDCl₃) δ: 0.32–0.54 (4H, m), 0.97–1.13 (1H, m), 1.48 (3H, t,J=7.2 Hz), 4.33 (2H, d, J=6.6 Hz), 4.52 (2H, d, J=7.2 Hz), 7.78 (1H, dd,J=2.0, 8.5 Hz), 8.29 (1H, d, J=8.5 Hz), 8.30 (1H, d, J=2.0 Hz), 11.16(1H, s).

(2) To a solution of ethyl6-bromo-2-cyclopropylmethyl-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(7.32 g, 20 mmol), 1-butanol (2.7 mL, 30 mmol) and tributylphosphine(10.0 mL, 40 mmol) in tetrahydrofuran (100 mL) was added1,1′-(azodicarbonyl)dipiperidine (10.09 g, 40 mmol) and the mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified, bysilica gel column chromatography to give ethyl6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(7.24 g, 85.8%) as an oil.

¹H-NMR(CDCl₃) δ: 0.39–0.57 (4H, m), 1.02 (3H, t, J=7.1 Hz), 1.13–1.31(1H, m), 1.45 (3H, t, J=7.2 Hz), 1.46–1.63 (2H, m), 1.73–1.87 (2H, m),3.90 (2H, d, J=7.0 Hz), 3.96 (2H, t, J=6.6 Hz), 4.47 (2H, q, J=7.2 Hz),7.65 (1H, dd, J=2.0, 8.6 Hz), 7.78 (1H, d, J=2.0 Hz), 8.29 (1H, dd,J=5.4, 8.6 Hz).

(3) To a solution of ethyl6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(7.18 g, 17 mmol) in tetrahydrofuran (20 mL) and ethanol (20 mL) wasadded an aqueous solution (10 mL) of sodium hydroxide (2.04 g, 51 mmol).The obtained mixture was refluxed under heating for 12 h. The reactionmixture was poured into water, acidified with 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals was recrystallized from ethylacetate-diisopropyl ether to give6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (6.41 g, 95.7%) as crystals.

Melting point 166–167° C. Elemental analysis for C₁₈H₂₀NO₄Br Calculated:C, 54.84; H, 5.11; N, 3.55. Found: C, 54.78; H, 4.98; N, 3.27.¹H-NMR(CDCl₃) δ: 0.41–0.57 (4H, m), 1.00 (3H, t, J=7.4 Hz), 1.22–1.35(1H, m), 1.45–1.63 (2H, m), 1.75–1.89 (2H, m), 3.98–4.08 (4H, m), 7.63(1H, dd, J=1.8, 8.8 Hz), 7.68 (1H, bs), 7.82 (1H, d, J=1.8 Hz), 8.24(1H, d, J=8.8 Hz).

(4) To a solution of6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (6.31 g, 16 mmol) in tetrahydrofuran (50 mL were added oxalylchloride (1.7 mL, 19.2 mmol) and N,N-dimethylformamide (2 drops), andthe mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL). The obtained solution was addeddropwise to a suspension of sodium tetrahydroborate (2.11 g, 56 mmol) in1,2-dimethoxyethane (30 mL) at 0° C. The obtained mixture was stirred at0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give6-bromo-4-butoxy-2-cyclopropylmethyl-3-hydroxymethyl-1(2H)-isoquinolinone(5.87 g, 96.5%) as crystals.

Melting point 111–112° C. Elemental analysis for C₁₈H₂₂NO₃Br Calculated:C, 56.85; H, 5.83; N, 3.68. Found: C, 56.69; H, 5.67; N, 3.59.¹H-NMR(CDCl₃) δ: 0.42–0.58 (4H, m), 1.04 (3H, t, J=7.1 Hz), 1.12–1.25(1H, m), 1.49–1.68 (2H, m), 1.79–1.93 (2H, m), 2.48 (1H, bs), 3.88 (2H,t, J=6.6 Hz), 4.19 (2H, d, J=6.6 Hz), 4.83 (2H, s), 7.56 (1H, dd, J=2.0,8.6 Hz), 7.79 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=8.8 Hz).

(5) To a solution of6-bromo-4-butoxy-2-cyclopropylmethyl-3-hydroxymethyl-1(2H)-isoquinolinone(5.70 g, 15 mmol) in toluene (50 mL) was added thionyl chloride (2.2 mL,30 mmol). The obtained mixture was refluxed under heating for 2 h. Thereaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution, and extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure to give6-bromo-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone(5.72 g, 95.7%) as crystals.

¹H-NMR(CDCl₃) δ: 0.44–0.61 (4H, m), 1.02–1.30 (4H, m), 1.53–1.68 (2H,m), 1.71–1.97 (2H, m), 4.00 (2H, t, J=6.4 Hz), 4.21 (2H, d, J=6.6 Hz),4.84 (2H, s), 7.63 (1H, dd, J=1.8, 8.4 Hz), 7.88 (1H, d, J=1.8 Hz), 8.29(1H, d, J=8.4 Hz).

(6) A solution of6-bromo-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone(5.58 g, 14 mmol) and potassium phthalimide (3.89 g, 21 mmol) inN,N-dimethylformamide (50 mL) was stirred at room temperature for 5 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-n-hexane to give2-[(6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(6.57 g, 94.7%) as crystals.

Melting point 156–157° C. Elemental analysis for C₂₆H₂₅N₂O₄BrCalculated: C, 61.30; H, 4.95; N, 5.50. Found: C, 61.39; H, 5.06; N,5.47. ¹H-NMR(CDCl₃) δ: 0.45–0.50 (4H, m), 0.97–1.08 (4H, m), 1.44–1.61(1H, m), 1.79–1.93 (2H, m), 3.99 (2H, t, J=6.7 Hz), 4.16 (2H, d, J=6.2Hz), 5.07 (2H, s), 7.59 (1H, dd, J=2.0, 8.8 Hz), 7.71–7.85 (4H, m) 7.86(1H, d, J=2.0 Hz), 8.27 (1H, d, J=8.8 Hz).

(7) To a solution of2-[(6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(6.62 g, 13 mmol) in ethanol (50 mL) was added hydrazine monohydrate(0.13 mL, 2.7 mmol). The obtained mixture was refluxed under heating for1 h. The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL) and di-t-butyl dicarbonate (4.5 mL, 19.5 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-n-hexane to givetert-butyl(6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(4.41 g, 70.8%) as crystals.

Melting point 118–119° C. Elemental analysis for C₂₃H₃₁N₂O₄BrCalculated: C, 57.62; H, 6.52; N, 5.84. Found: C, 57.79; H, 6.37; N,5.71. ¹H-NMR(CDCl₃) δ: 0.50–0.55 (4H, m), 1.05 (3H, t, J=7.3 Hz),1.13–1.26 (1H, m), 1.46 (9H, s), 1.47–1.68 (2H, m), 1.80–1.94 (2H, m),3.86 (2H, t, J=6.5 Hz), 4.09 (2H, d, J=7.0 Hz), 4.53 (2H, d, J=5.6 Hz),4.79 (1H, bs), 7.58 (1H, dd, J=2.0, 8, 6 Hz), 7.82 (1H, d, J=2.0 Hz),8.26 (1H, d, J=8.6 Hz).

(8) A mixture oftert-butyl(6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-methylcarbamate(4.08 g, 8.5 mmol), 1,3-bis(diphenylphosphino)propane (0.35 g, 0.85mmol) and triethylamine (1.3 mL, 9.4 mmol) in dimethyl sulfoxide (60 mL)and methanol (40 mL) was stirred under a carbon monoxide atmosphere atroom temperature for 30 min. To the obtained mixture was added palladiumacetate (0.19 g, 0.85 mmol) and the mixture was stirred under a carbonmonoxide atmosphere at 70° C. for 15 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. After washing the extractwith water, the extract was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give methyl4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(3.41 g, 87.7%) as crystals.

Melting point 139–140° C. Elemental analysis for C₂₅H₃₄N₂O₆ Calculated:C, 65.48; H, 7.47; N, 6.11. Found: C, 65.59; H, 7.53; N, 6.13.¹H-NMR(CDCl₃) δ: 0.52–0.55 (4H, m), 1.06 (3H, t, J=7.4 Hz), 1.15–1.30(1H, m), 1.46 (9H, s), 1.53–1.68 (2H, m), 1.83–1.97 (2H, m), 3.91 (2H,t, J=6.4 Hz), 3.99 (3H, s), 3.91 (2H, d, J=6.6 Hz), 4.56 (2H, d, J=5.4Hz), 4.81 (1H, bs), 8.09 (1H, dd, J=1.6, 8.4 Hz), 8.40 (1H, d, J=1.6Hz), 8.48 (1H, d, J=8.4 Hz,).

(9) To a solution of methyl4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(2.98 g, 6.5 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) wasadded 1N sodium hydroxide (10 mL). The obtained mixture was stirred atroom temperature for 2 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-diisopropyl ether to give4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (2.62 g, 90.7%) as crystals.

Melting point 197–198° C. Elemental analysis for C₂₄H₃₂N₂O₆ Calculated:C, 64.85; H, 7.26; N, 6.30. Found: C, 64.95; H, 7.26; N, 6.29.¹H-NMR(CDCl₃) δ: 0.51–0.53 (4H, m), 1.07 (3H, t, J=7.3 Hz), 1.13–1.30(1H, m), 1.50 (9H, s), 1.53–1.72 (2H, m), 1.85–1.99 (2H, m), 3.91 (2H,t, J=6.2 Hz), 4.09 (2H, d, J=6.6 Hz), 4.56 (2H, d, J=5.0 Hz), 4.47 (1H,bs), 8.08 (1H, d, J=8.5 Hz), 8.30 (1H, bs), 8.39 (1H, d, J=8.5 Hz).

(10) A solution4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (0.89 g, 2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.77 g, 4 mmol) and 1-hydroxybenzotriazole ammonium salt(0.61 g, 4 mmol) in N,N-dimethylformamide (10 mL) was stirred at roomtemperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(0.82 g, 93.2%) as crystals.

Melting point 202–203° C. Elemental analysis for C₂₄H₃₃N₃O₅ Calculated:C, 64.99; H, 7.50; N, 9.47. Found: C, 64.89; H, 7.68; N, 9.42.¹H-NMR(CDCl₃) δ: 0.52–0.56 (4H, m), 1.03 (3H, t, J=7.1 Hz), 1.18–1.29(1H, m), 1.48 (9H, s), 1.49–1.66 (2H, m), 1.86–1.94 (2H, m), 3.87 (2H,t, J=6.6 Hz), 4.10 (2H, d, J=6.6 Hz), 4.54 (2H, d, J=5.4 Hz), 5.24 (1H,bs), 6.03 (1H, bs), 6.60 (1H, bs), 7.72 (1H, dd, J=1.6, 8.4 Hz), 8.04(1H, d, J=1.6 Hz), 8.29 (1H, d, J=8.4 Hz).

(11) To a solution of4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(0.27 g, 0.6 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diethyl ether to give3-(aminomethyl)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamidehydrochloride (0.21 g, 91.3%) as crystals.

Melting point 164–165° C. Elemental analysis for C₁₉H₂₆N₃O₃Cl 0.5H₂OCalculated: C, 58.68; H, 7.00; N, 10.81. Found: C, 59.03; H, 6.85; N,10.82. ¹H-NMR(DMSO-d₆) δ: 0.45–0.49 (4H, m), 1.01 (3H, t, J=7.3 Hz),1.09–1.21 (1H, m), 1.52–1.63 (2H, m), 1.83–1.99 (2H, m), 3.99 (2H, t,J=5.9 Hz), 4.08 (2H, d, J=6.4 Hz), 4.23 (2H, s), 7.71 (1H, s), 8.05 (1H,d, J=8.2 Hz), 8.23 (1H, s), 8.33 (1H, d, J=8.2 Hz), 8.38 (1H, s), 8.68(3H, bs).

Example 1473-(Aminomethyl)-4-butoxy-2-cyclopropylmethyl-6-(1,3-oxazol-5-yl)-1(2H)-isoquinolinonehydrochloride

(1) To a solution of4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (Example 146 (9)) (0.45 g, 3.5 mmol) and N-methylmorpholine (0.13mL, 1.2 mmol) in tetrahydrofuran (10 mL) was added ethyl chloroformate(0.12 mL, 1.2 mmol) at 0° C. and the mixture was stirred at 0° C. for 10min. To the obtained mixture were added sodium tetrahydroborate (0.11 g,3 mmol) and methanol (5 mL), and the mixture was stirred at 0° C. for 1h. The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. Theprecipitated crystals were recrystallized from ethyl acetate-diisopropylether to givetert-butyl(4-butoxy-2-cyclopropylmethyl-6-hydroxymethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.33 g, 76.7%) as crystals.

Melting point 171–172° C. Elemental analysis for C₂₄H₃₄N₂O₅ Calculated:C, 66.95; H, 7.96; N, 6.51. Found: C, 66.65; H, 7.82; N, 6.63.¹H-NMR(CDCl₃) δ: 0.51–0.56 (4H, m), 1.00 (3H, t, J=7.3 Hz), 1.19–1.26(1H, m), 1.49–1.57 (11H, m), 1.79–1.93 (2H, m), 2.27 (1H, bs), 3.82 (2H,t, J=6.8 Hz), 4.07 (2H, d, J=6.6 Hz), 4.51 (2H, d, J=5.4 Hz), 4.80 (2H,s), 5.53 (1H, s), 7.38 (1H, d, J=8.2 Hz), 7.46 (1H, s), 8.13 (1H, d,J=8.2 Hz).

(2) To a solution of 4tert-butyl(4-butoxy-2-cyclopropylmethyl-6-hydroxymethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.45 g, 3.5 mmol) in tetrahydrofuran (10 mL) was added manganesedioxide (0.12 g) and the mixture was stirred at room temperature for 12h. Manganese dioxide was filtered off, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to givetert-butyl(4-butoxy-2-cyclopropylmethyl-6-formyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.33 g, 76.7%) as crystals.

Melting point 151–152° C. Elemental analysis for C₂₄H₃₂N₂O₅ Calculated:C, 67.27; H, 7.53; N, 6.54. Found: C, 67.08; H, 7.55; N, 6.54.¹H-NMR(CDCl₃) δ: 0.53–0.56 (4H, m), 1.06 (3H, t, J=7.3 Hz), 1.16–1.28(1H, m), 1.47 (9H, s), 1.55–1.68 (2H, m), 1.87–1.96 (2H, m), 3.92 (2H,t, J=6.4 Hz), 4.14 (2H, d, J=6.6 Hz), 4.57 (2H, d, J=5.7 Hz), 4.82 (1H,bs), 7.96 (1H, dd, J=1.8, 8.4 Hz), 8.19 (1H, d, J=1.8 Hz), 8.57 (1H, d,J=8.4 Hz), 10.19 (1H, s).

(3) A solution oftert-butyl(4-butoxy-2-cyclopropylmethyl-6-formyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.34 g, 0.8 mmol) p-toluenesulfonylmethyl isocyanide (0.16 g, 0.8 mmol)and potassium carbonate (0.22 g, 1.6 mmol) in methanol (10 mL) wasrefluxed under heating for 30 min. The reaction mixture was poured intowater and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography and the precipitated crystals were recrystallized fromethyl acetate-diisopropyl ether to givetert-butyl[4-butoxy-2-cyclopropylmethyl-6-(1,3-oxazol-5-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.33 g, 76.7%), as crystals.

Melting point 160–161° C. Elemental analysis for C₂₆H₃₃N₃O₅ Calculated:C, 66.79; H, 7.11; N, 8.99. Found: C, 66.63; H, 7.14; N, 9.01.¹H-NMR(CDCl₃) δ: 0.52–0.56 (4H, m), 1.07 (3H, t, J=7.2 Hz), 1.12–1.26(1H, m), 1.47 (9H, s), 1.58–1.71 (2H, m), 1.87–1.96 (2H, m), 3.92 (2H,t, J=6.6 Hz), 4.12 (2H, d, J=6.6 Hz), 4.56 (2H, d, J=5.7 Hz), 4.84 (1H,bs), 7.53 (1H, s), 7.75 (1H, dd, J=1.5, 8.4 Hz), 7.97 (1H, d, J=1.5 Hz),8.02 (1H, s), 8.46 (1H, d, J=8.4 Hz).

(4) To a solution oftert-butyl[4-butoxy-2-cyclopropylmethyl-6-(1,3-oxazol-5-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.19 g, 0.4 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diethyl ether to give3-(aminomethyl)-4-butoxy-2-cyclopropylmethyl-6-(1,3-oxazol-5-yl)-1(2H)-isoquinolinonehydrochloride (0.15 g, 93.8%) as crystals.

Melting point 124–126° C. Elemental analysis for C₂₁H₂₆N₃O₃Cl 1.25H₂OCalculated: C, 59.15; H, 6.74; N, 9.85. Found: C, 59.12; H, 6.58; N,9.71. ¹H-NMR(DMSO-d₆) δ: 0.46–0.49 (4H, s), 1.03 (3H, t, J=7.2 Hz),1.15–1.28 (1H, m), 1.54–1.69 (2H, m), 1.83–1.95 (2H, m), 3.99 (2H, t,J=6.2 Hz), 4.08 (2H, d, J=6.6 Hz), 4.23 (2H, d, J=5.4 Hz), 7.99–8.01(3H, m), 8.36 (1H, d, J=9.2 Hz), 8.63 (1H, s), 8.74 (3H, bs).

Example 148(E)-3-[3-(Aminomethyl)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride

(1) To a solution of ethyl diethylphosphonoacetate (0.99 mL, 5 mmol) inN,N-dimethylformamide (30 mL) was added. sodium hydride (0.20 g, 5 mmol)(60% in oil) and the mixture was stirred at room temperature for 10 min.To the obtained mixture was added a solution of tert-butyl(4-butoxy-2-cyclopropylmethyl-6-formyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(Example 2 (2))(2.14 g, 5 mmol) in N,N-dimethylformamide (20 mL) and themixture was stirred at room temperature for 3 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give ethyl(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenate(1.92 g, 77.1%) as crystals.

Melting point 166–167° C. Elemental analysis for C₂₈H₃₈N₂O₆ Calculated:C, 67.45; H, 7.68; N, 5.62. Found: C, 67.40; H, 7.65; N, 5.44.¹H-NMR(CDCl₃) δ: 0.51–0.55 (4H, m), 1.06 (3H, t, J=7.1 Hz), 1.14–1.27(1H, m), 1.37 (3H, t, J=7.2 Hz), 1.46 (9H, s), 1.47–1.69 (2H, m),1.83–1.97 (2H, m), 3.89 (2H, t, J=6.4 Hz), 4.12 (2H, d, J=6.6 Hz), 4.30(2H, q, J=7.2 Hz), 4.55 (2H, d, J=5.4 Hz), 4.78 (1H, bs), 6.58 (1H, d,J=15.8 Hz), 7.66 (1H, dd, J=1.8, 8.4 Hz), 7.78 (1H, d, J=1.8 Hz), 7.79(1H, d, J=15.8 Hz), 8.42 (1H, d, J=8.4 Hz).

(2) To a solution of ethyl(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenate(1.00 g, 2 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) wasadded 1N sodium hydroxide (4 mL). The obtained mixture was stirred atroom temperature for 2 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from tetrahydrofuran-diisopropyl ether to give(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenicacid (0.92 g, 97.9%) as crystals.

Melting point 229–230° C. Elemental analysis for C₂₆H₃₄N₂O₆ Calculated:C, 66.36; H, 7.28; N, 5.95. Found: C, 66.05; H, 7.22; N, 5.66.¹H-NMR(CDCl₃) δ: 0.50–0.55 (4H, m), 1.07 (3H, t, J=7.3 Hz), 1.12–1.28(1H, m), 1.48 (9H, s), 1.49–1.70 (2H, m), 1.84–1.98 (2H, m), 3.89 (2H,t, J=6.6 Hz), 4.10 (2H, d, J=6.6 Hz), 4.55 (2H, d, J=5.0 Hz), 5.12 (1H,bs), 6.59 (1H, d, J=16.0 Hz), 7.64 (1H, d, J=8.2 Hz), 7.73 (1H, s), 7.85(1H, d, J=16.0 Hz), 8.38 (1H, d, J=8.2 Hz).

(3) A solution of(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenicacid (0.71 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt(0.46 g, 3 mmol) in N,N-dimethylformamide (10 mL) was stirred at roomtemperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide(0.67 g, 95.7%) as crystals.

Melting point 198–199° C. Elemental analysis for C₂₆H₃₅N₃O₅ 0.5H₂OCalculated: C, 65.87; H, 7.55; N, 8.86. Found: C, 65.86; H, 7.89; N,8.68. ¹H-NMR(CDCl₃) δ: 0.50–0.54 (4H, m), 1.04 (3H, t, J=7.4 Hz),1.12–1.26 (1H, m), 1.47 (9H, s), 1.48–1.67 (2H, m), 1.81–1.95 (2H, m),3.88 (2H, t, J=6.4 Hz), 4.10 (2H, d, J=6.6 Hz), 4.54 (2H, d, J=5.2 Hz),5.40 (1H, bs); 5.89 (1H, bs), 6.05 (1H, bs), 6.60 (1H, d, J=15.8 Hz),7.56 (1H, dd, J=1.5, 8.4 Hz), 7.69 (1H, d, J=1.5 Hz), 7.73 (1H, d,J=15.8 Hz), 8.31 (1H, d, J=8.4 Hz).

(4) To a solution of(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-1-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide(0.38 g, 0.8 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diisopropyl ether to give(E)-3-[3-(aminomethyl)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride (0.31 g, 96.9%) as crystals.

Melting point 188–190° C. Elemental analysis for C₂₁H₂₈N₃O₃Cl 2H₂OCalculated: C, 57.07; H, 7.30; N, 9.51. Found: C, 56.82; H, 7.06; N,9.49. ¹H-NMR(DMSO-d₆) δ: 0.45–0.48 (4H, m), 1.02 (3H, t, J=6.9 Hz),1.13–1.24 (1H, m), 1.47–1.69 (2H, m), 1.79–1.99 (2H, m), 4.05 (2H, bs),4.22 (2H, bs), 4.32 (2H, bs), 6.85 (1H, d, J=15.4 Hz), 7.28 (1H, bs),7.63 (1H, d, J=15.4 Hz), 7.80–7.88 (3H, m), 8.30 (1H, d, J=7.0 Hz), 8.68(3H, bs).

Example 1492-[[3-(Aminomethyl)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride

(1) A solution of 4-fluorophthalic anhydride (24.99 g, 150 mmol) andethyl 2-(cyclopropylmethylamino)acetate (23.58 g, 150 mmol) intetrahydrofuran (200 mL) was stirred at room temperature for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wasdissolved, in N,N-dimethylformamide (200 mL) and potassium carbonate(20.73 g, 150 mmol) and ethyl iodide (14.4 mL, 180 mmol) were added. Themixture was stirred at room temperature for 3 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved inethanol (300 mL) and a solution of 20% sodium ethoxide ethanol solution(102 g, 300 mmol) was added thereto. The mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into 1Nhydrochloric acid (300 mL) and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography and the component eluted earlier wasconcentrated to give ethyl2-cyclopropylmethyl-7-fluoro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(13.11 g, 28.6%) as crystals.

Melting point 88–89° C. Elemental analysis for C₁₆H₁₆NO₄F Calculated: C,62.94; H, 5.28; N, 4.59. Found: C, 62.96; H, 5.23; N, 4.61.¹H-NMR(CDCl₃) δ: 0.34–0.52 (4H, m), 1.04–1.13 (1H, m), 1.48 (3H, t,J=7.2 Hz), 4.35 (2H, d, J=6.9 Hz), 4.51 (2H, d, J=7.2 Hz), 7.44–7.50(1H, m), 8.09 (1H, dd, J=2.6, 6.2 Hz), 8.19 (1H, dd, J=6.2, 8.4 Hz),11.36 (1H, s).

The component eluted later was concentrated to give ethyl2-cyclopropylmethyl-6-fluoro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(9.34 g, 20.4%) as crystals.

Melting point 61–62° C. Elemental analysis for C₁₆H₁₆NO₄F Calculated: C,62.94; H, 5.28; N, 4.59. Found: C, 62.75; H, 5.14; N, 4.64.¹H-NMR(CDCl₃) δ: 0.32–0.54 (4H, m), 1.00–1.16 (1H, m), 1.48 (3H, t,J=7.2 Hz), 4.33 (2H, d, J=7.0 Hz), 4.52 (2H, d, J=7.2 Hz), 7.33–7.43(1H, m), 7.78 (1H, dd, J=2.6, 9.2 Hz), 8.46 (1H, dd, J=5.4, 8.8 Hz),11.14 (1H, s).

(2) To a solution of ethyl2-cyclopropylmethyl-6-fluoro-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(9.16 g, 30 mmol), 1-butanol (3.3 mL, 45 mmol) and tributylphosphine(14.9 mL, 60 mmol) in tetrahydrofuran (100 mL) was added1,1′-(azodicarbonyl)dipiperidine (15.14 g, 60 mmol) and the mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography to give ethyl4-butoxy-2-cyclopropylmethyl-6-fluoro-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(9.24 g, 85.2%) as an oil.

¹H-NMR(CDCl₃) δ: 0.39–0.57 (4H, m), 1.01 (3H, t, J=7.3 Hz), 1.12–1.21(1H, m), 1.41–1.62 (5H, m), 1.73–1.87 (2H, m), 3.91 (2H, d, J=6.8 Hz),3.96 (2H, t, J=6.6 Hz), 4.47 (2H, q, J=7.3 Hz), 7.19–7.30 (1H, m), 8.73(1H, dd, J=2.4, 9.4 Hz), 8.46 (1H, dd, J=5.4, 8.8 Hz).

(3) To a solution of ethyl4-butoxy-2-cyclopropylmethyl-6-fluoro-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(9.03 g, 25 mmol) in tetrahydrofuran (30 mL) and ethanol (30 mL) wasadded sodium hydroxide (3.00 g, 75 mmol). The obtained mixture wasrefluxed under heating for 12 h. The reaction mixture was poured intowater, acidified with 1N hydrochloric acid and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in benzyl alcohol (20 mL) and the obtained solution wasadded dropwise to a solution of sodium hydride (5.0 g, 125 mmol)(60% inoil) in benzyl alcohol (20 mL). The obtained mixture was stirred at 150°C. for 12 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (7.31 g, 69.4%) as crystals.

Melting point 178–179° C. Elemental analysis for C₂₅H₂₇NO₅ Calculated:C, 71.24; H, 6.46; N, 3.32. Found: C, 71.21; H, 6.68; N, 3.23.¹H-NMR(CDCl₃) δ: 0.41–0.52 (4H, m), 0.97 (3H, t, J=7.4 Hz), 1.18–1.32(1H, m), 1.38–1.57 (2H, m), 1.67–1.80 (2H, m), 3.88 (2H, t, J=6.4 Hz),4.00 (2H, d, J=7.0 Hz), 5.17 (2H, s), 6.55 (1H, bs), 6.98 (1H, d, J=2.5Hz), 7.16 (1H, dd, J=2.5, 8.8 Hz), 7.30–7.44 (5H, m), 8.25 (1H, d, J=8.8Hz).

(4) To a solution of6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (7.16 g, 17 mmol) in tetrahydrofuran (50 mL) were added oxalylchloride (1.8 mL, 20.4 mmol) and N,N-dimethylformamide (3 drops), andthe mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (30 mL). The obtained solution was addeddropwise to a suspension of sodium tetrahydroborate (2.25 g, 59.5 mmol)in 1,2-dimethoxyethane (50 mL) at 0° C. The obtained mixture was stirredat 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloricacid and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The obtained crystals were recrystallized from ethylacetate-n-hexane to give6-benzyloxy-4-butoxy-2-cyclopropylmethyl-3-hydroxymethyl-1(2H)-isoquinolinone(1.72 g, 57.1%) as crystals.

Melting point 96–97° C. Elemental analysis for C₂₅H₂₉NO₄ Calculated: C,73.68; H, 7.17; N, 3.44. Found: C, 73.53; H, 7.10; N, 3.39.¹H-NMR(CDCl₃) δ: 0.45–0.55 (4H, m), 1.02 (3H, t, J=7.3 Hz), 1.12–1.24(1H, m), 1.44–1.62 (2H, m), 1.72–1.86 (2H, m), 3.79 (2H, t, J=6.6 Hz),4.17 (2H, d, J=6.4 Hz), 4.82 (2H, d, J=5.2 Hz), 5.19 (2H, s), 7.05 (1H,d, J=2.6 Hz), 7.11 (1H, dd, J=2.6, 8.8 Hz), 7.31–7.48 (5H, m), 8.28 (1H,d, J=8.8 Hz).

(5) To a suspension of6-benzyloxy-4-butoxy-2-cyclopropylmethyl-3-hydroxymethyl-1(2H)-isoquinolinone(6.11 g, 15 mmol) in toluene (50 mL) was added thionyl chloride (2.2.mL, 30 mmol). The obtained mixture was refluxed under heating for 2 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-benzyloxy-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone(6.17 g, 96.7%) as crystals.

¹H-NMR(CDCl₃) δ: 0.47–0.55 (4H, m), 1.03 (3H, t, J=7.5 Hz), 1.06–1.18(1H, m), 1.48–1.63 (2H, m), 1.79–1.86 (2H, m), 3.90 (2H, t, J=6.6 Hz),4.20 (2H, d, J=6.6 Hz), 4.84 (2H, s), 5.22 (2H, s), 7.14–7.26 (2H, m),7.34–7.47 (5H, m), 8.36 (1H, d, J=9.0 Hz).

(6) A solution of6-benzyloxy-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone(5.96 g, 14, mmol) and potassium phthalimide (3.89 g, 21 mmol) inN,N-dimethylformamide (50 mL) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give2-[(6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(7.14 g, 95.1%) as crystals.

Melting point 127–128° C. Elemental analysis for C₃₃H₃₂N₂O₅ Calculated:C, 73.86; H, 6.01; N, 5.22. Found: C, 73.73; H, 5.79; N, 5.22.¹H-NMR(CDCl₃) δ: 0.43–0.48 (4H, m), 0.97 (3H, t, J=7.3 Hz), 1.01–1.04(1H, m), 1.37–1.55 (2H, m), 1.71–1.86 (2H, m), 3.89 (2H, t, J=6.8 Hz),4.15 (2H, d, J=6.2 Hz), 5.06 (2H, s), 5.20 (2H, s), 7.12–7.17 (2H, m),7.30–7.46 (5H, m), 7.70–7.86 (4H, m), 8.32–8.38 (1H, m).

(7) To a solution of2-[(6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(6.97 g, 13 mmol) in ethanol (50 mL) was added hydrazine monohydrate(1.9 mL, 39 mmol). The obtained mixture was refluxed under heating for 2h. The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (50 mL) and di-t-butyl dicarbonate (4.5 mL, 19.5 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-n-hexane to givetert-butyl(6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(6.34 g, 96.4%) as crystals.

Melting point 106–107° C. Elemental analysis for C₃₀H₃₈N₂O₅ 0.25H₂OCalculated: C, 70.50; H, 7.59; N, 5.48. Found: C, 70.61; H, 7.48; N,5.45. ¹H-NMR(CDCl₃) δ: 0.49–0.52 (4H, m), 1.02 (3H, t, J=7.3 Hz),1.15–1.26 (1H, m), 1.46 (9H, s), 1.51–1.62 (2H, m), 1.72–1.87 (2H, m),3.77 (2H, t, J=6.5 Hz), 4.08 (2H, d, J=5.6 Hz), 4.51 (2H, d, J=5.6 Hz),4.79 (1H, bs), 5.21 (2H, s), 7.07 (1H, d, J=2.6 Hz), 7.14 (1H, dd,J=2.6, 8.8 Hz), 7.33–7.49 (5H, m), 8.34 (1H, d, J=8.8 Hz).

(8) A suspension oftert-butyl(6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-methylcarbamate(6.08 g, 12 mmol) and 5% palladium carbon (2.0 g), in tetrahydrofuran(30 mL) and ethanol (30 mL) was stirred under a hydrogen atmosphere atroom temperature for 2 h. The catalyst was filtered off and the filtratewas concentrated under reduced pressure. The obtained crystals wererecrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl(4-butoxy-2-cyclopropylmethyl-6-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(4.87 g, 97.6%) as crystals.

Melting point 164–166° C. Elemental analysis for C₂₃H₃₂N₂O₅ Calculated:C, 66.32; H, 7.74; N, 6.73. Found: C, 66.16; H, 7.69; N, 6.82.¹H-NMR(CDCl₃) δ: 0.48–0.52 (4H, m), 0.96 (3H, t, J=7.4 Hz), 1.13–1.26(1H, m), 1.45–1.58 (11H, m), 1.69–1.84 (2H, m), 3.83 (2H, t, J=6.2 Hz),4.12 (2H, d, J=6.6 Hz), 4.53 (2H, d, J=5.2 Hz), 4.89 (1H, bs), 7.06–7.12(2H, m), 8.25 (1H, d, J=8.4 Hz), 9.24 (1H, bs).

(9) A solution oftert-butyl(4-butoxy-2-cyclopropylmethyl-6-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.42 g, 1 mmol), 2-iodoacetamide (0.27 g, 1.5 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.22 mL, 1.5 mmol) inN,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[6-(2-amino-2-oxoethoxy)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl]-methylcarbamate(0.36 g, 76.6%) as crystals.

Melting point 209–210° C. Elemental analysis for C₂₅H₃₅N₃O₆ Calculated:C, 63.41; H, 7.45; N, 8.87. Found: C, 63.05; H, 7.31; N, 8.61.¹H-NMR(CDCl₃) δ: 0.48–0.56 (4H, m), 1.04 (3H, t, J=7.2 Hz), 1.15–1.26(1H, m), 1.46 (9H, s), 1.48–1.69 (2H, m), 1.80–1.91 (2H, m), 3.86 (2H,t, J=6.4 Hz), 4.09 (2H, d, J=6.6 Hz), 4.53 (2H, d, J=5.6 Hz), 4.62 (2H,s), 4.86 (1H, bs), 5.89 (1H, bs), 6.62 (1H, bs), 7.06–7.12 (2H, m), 8.36(1H, d, J=9.2 Hz).

(10) To a solution oftert-butyl[6-(2-amino-2-oxoethoxy)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.28 g, 0.6 mmol) in ethyl acetate (5 mL) was added a-solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diisopropyl ether to give2-[[3-(aminomethyl)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride (0.23 g, 92.0%) as crystals.

Melting point 133–134° C. Elemental analysis for C₂₀H₂₈N₃O₄Cl 1.5H₂OCalculated: C, 54.98; H, 7.15; N, 9.62. Found: C, 54.84; H, 6.90; N,9.54. ¹H-NMR(DMSO d₆) δ: 0.43–0.46 (4H, m), 1.00 (3H, t, J=7.1 Hz),1.12–1.21 (1H, m), 1.50–1.63 (2H, m), 1.81–1.92 (2H, m), 3.93 (2H, t,J=6.1 Hz), 4.04 (2H, d, J=6.2 Hz), 4.18 (2H, s), 4.64 (2H, s), 7.23 (1H,d, J=8.8 Hz), 7.47 (1H, s), 7.75 (1H, s), 8.21 (1H, d, J=8.8 Hz), 8.68(3H, s).

Example 1502-[[3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride

(1) A solution of 4-fluorophthalic anhydride (24.99 g, 150 mmol) andethyl 2-(isobutylamino)acetate (23.88 g, 150 mmol) in tetrahydrofuran(200 mL) was stirred at room temperature for 1 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (200 mL), and potassium carbonate (20.73 g, 150mmol) and ethyl iodide (14.4 mL, 180 mmol) were added thereto. Themixture was stirred at room temperature for 3 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved inethanol (300 mL) and a solution of 20% sodium ethoxide ethanol solution(102 g, 300 mmol) was added thereto. The mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into 1Nhydrochloric acid (300 mL) and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography and the component eluted earlier wasconcentrated to give ethyl7-fluoro-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(19.2 g, 41.7%) as crystals.

Melting point 104–105° C. Elemental analysis for C₁₆H₁₈NO₄F Calculated:C, 62.53; H, 5.90; N, 4.56. Found: C, 62.81; H, 5.99; N, 4.67.¹H-NMR(CDCl₃) δ: 0.82 (6H, d, J=6.6 Hz), 1.46 (3H, t, J=7.2 Hz,),1.76–1.89 (1H, m), 4.41 (2H, d, J=7.2 Hz), 4.49 (2H, d, J=7.2 Hz),7.43–7.50 (1H, m), 8.08–8.21 (2H, m), 11.34 (1H, s).

The component eluted later was concentrated to give ethyl6-fluoro-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(13.41 g, 29.1%) as crystals.

Melting point 91–92° C. Elemental analysis for C₁₆H₁₈NO₄F Calculated: C,62.53; H, 5.90; N, 4.56. Found: C, 62.73; H, 5.83; N, 4.53.¹H-NMR(CDCl₃) δ: 0.82 (6H, d, J=6.6 Hz), 1.46 (3H, t, J=7.2 Hz),1.74–1.86 (1H, m), 4.40 (2H, d, J=7.5 Hz), 4.49 (2H, d, J=7.2 Hz),7.34–7.42 (1H, m), 7.75–7.80 (1H, m), 8.45–8.51 (1H, m), 11.12 (1H, s).

(2) To a solution of ethyl6-fluoro-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(9.22 g, 30 mmol), 1-butanol (3.3 mL, 45 mmol) and tributylphosphine(14.9 mL, 60 mmol) in tetrahydrofuran (100 mL) was added1,1′-(azodicarbonyl)dipiperidine (15.14 g, 60 mmol) and the mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give ethyl4-butoxy-6-fluoro-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(9.25 g, 84.9%) as an oil.

¹H-NMR(CDCl₃) δ: 0.91 (6H, d, J=6.6 Hz), 1.01 (3H, t, J=7.4 Hz), 1.45(3H, t, J=7.2 Hz), 1.46–1.66 (2H, m), 1.74–1.84 (2H, m), 2.05–2.18 (1H,m), 3.88 (2H, d, J=7.8 Hz), 3.95 (2H, t, J=6.6 Hz), 4.46 (2H, q, J=7.2Hz), 7.27–7.29 (1H, m), 7.34–7.38 (1H, m), 8.44–8.48 (1H, m).

(3) To a solution of ethyl4-butoxy-6-fluoro-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(9.09 g, 25 mmol) in tetrahydrofuran (30 mL) and ethanol (30 mL) wasadded sodium hydroxide (3.00 g, 75 mmol). The obtained mixture wasrefluxed under heating for 12 h. The reaction mixture was poured intowater, acidified with 1N hydrochloric acid and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in benzyl alcohol (20 mL) and the obtained solution wasadded dropwise to a solution of sodium hydride (5.0 g, 125 mmol)(60% inoil) in benzyl alcohol (20 mL). The obtained mixture was stirred at 150°C. for 12 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (9.32 g, 88.1%) as crystals.

Melting point 151–152° C. Elemental analysis for C₂₅H₂₉NO₅ Calculated:C, 70.90; H, 6.90; N, 3.31. Found: C, 70.89; H, 6.91; N, 3.37.¹H-NMR(CDCl₃) δ: 0.85 (6H, d, J=7.0 Hz), 0.98 (3H, t, J=7.3 Hz),1.39–1.58 (2H, m), 1.67–1.81 (2H, m), 2.06–2.19 (1H, m), 3.89 (2H, t,J=6.6 Hz), 3.95 (2H, d, J=7.8 Hz), 5.16 (2H, s) 6.96 (1H, d, J=2.6 Hz),7.17 (1H, dd, J=2.6, 9.0 Hz), 7.32–7.45 (5H, m), 8.23 (1H, d, J=9.0 Hz).

(4) To a solution of6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (7.62 g, 18 mmol) in tetrahydrofuran (50 mL) were added oxalylchloride (1.9 mL, 21.6 mmol) and N,N-dimethylformamide (2 drops), andthe mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (30 mL). The obtained solution was addeddropwise to a suspension of sodium tetrahydroborate (2.38 g, 63 mmol) in1,2-dimethoxyethane (50 mL) at 0° C. The obtained mixture was stirred at0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give6-benzyloxy-4-butoxy-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(7.11 g, 96.5%) as crystals.

Melting point 90–91° C. Elemental analysis for C₂₅H₃₁NO₄0.25H₂OCalculated: C, 72.53; H, 7.67; N, 3.38. Found: C, 72.86; H, 7.71; N,3.31. ¹H-NMR(CDCl₃) δ: 0.92 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.1 Hz),1.48–1.60 (2H, m), 1.72–1.85 (2H, m), 2.11–2.25 (1H, m), 2.44 (1H, bs),3.79 (2H, t, J=6.4 Hz), 4.05 (2H, d, J=7.4 Hz), 4.79 (2H, d, J=5.4 Hz),5.19 (2H, s), 7.06–7.13 (2H, m), 7.34–7.45 (4H, m), 8.28 (1H, d, J=8.4Hz).

(5) To a suspension of6-benzyloxy-4-butoxy-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(6.96 g, 17 mmol) in toluene (50 mL)) was added thionyl chloride (2.5mL, 34 mmol). The obtained mixture was refluxed under heating for 2 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-benzyloxy-4-butoxy-3-chloromethyl-2-isobutyl-1(2H)-isoquinolinone(6.90 g, 94.8%) as crystals.

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=7.0 Hz), 1.03 (3H, t, J=7.3 Hz),1.47–1.65 (2H, m), 1.76–1.90 (2H, m), 2.09–2.23 (1H, m), 3.88 (2H, t,J=6.4 Hz), 4.05 (2H, d, J=7.2 Hz), 4.80 (2H, s), 5.21 (2H, s), 7.13–7.47(7H, m) 8.36 (1H, d, J=8.8 Hz).

(6) A solution of6-benzyloxy-4-butoxy-3-chloromethyl-2-isobutyl-1(2H)-isoquinolinone(6.85 g, 16 mmol) and potassium phthalimide (4.44 g, 24 mmol) inN,N-dimethylformamide (50 mL) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give2-[(6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(7.08 g, 82.2%) as an amorphous.

¹H-NMR(CDCl₃) δ: 0.93–1.01 (,9H, m), 1.41–1.55 (2H, m), 1.71–1.85 (2H,m), 2.05–2.22 (1H, m), 3.89 (2H, t, J=6.9 Hz), 4.01 (2H, d, J=7.2 Hz),5.01 (2H, s), 5.20 (2H, s), 7.13–7.17 (2H, m), 7.30–7.46 (5H, m),7.68–7.87 (2H, m), 8.32–8.36 (1H, m).

(7) To a solution of2-[(6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(7.00 g, 13 mmol) in ethanol (50 mL) was added hydrazine monohydrate(1.9 mL, 39 mmol). The obtained mixture was refluxed under heating for 2h. The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (50 mL) and di-t-butyl dicarbonate (4.5 mL, 19.5 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-n-hexane to givetert-butyl(6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(6.44 g, 97.4%) as crystals.

Melting point 104–105° C. Elemental analysis for C₃₀H₄₀N₂O₅ Calculated:C, 70.84; H, 7.93; N, 5.51. Found: C, 70.85; H, 7.70; N, 5.48.¹H-NMR(CDCl₃) δ: 0.94 (6H, d, J=7.0 Hz), 1.02 (3H, t, J=7.3 Hz),1.46–1.62 (11H, m), 1.72–1.86 (2H, m), 2.05–2.22 (1H, m), 3.75 (2H, t,J=6.6 Hz), 3.96 (2H, d, J=7.6 Hz), 4.48 (2H, d, J=5.4 Hz), 4.73 (1H,bs), 5.21 (2H, s), 7.08 (1H, d, J=2.6 Hz), 7.15 (1H, dd, J=2.6, 8.8 Hz),7.30–7.47 (5H, m), 8.34 (1H, d, J=8.8 Hz).

(8) A suspension oftert-butyl(6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(6.10 g, 12 mmol) and 5% palladium carbon (2.0 g) in tetrahydrofuran (30mL) and ethanol (30 mL) was stirred under a hydrogen atmosphere at roomtemperature for 2 h. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The obtained crystals wererecrystallized from ethyl acetate-diisopropyl ether to give tert-butyl(4-butoxy-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(4.86 g, 96.8%) as crystals.

Melting point 185–186° C. Elemental analysis for C₂₃H₃₄N₂O₅ Calculated:C, 66.00; H, 8.19; N, 6.69. Found: C, 66.02; H, 8.14; N, 6.73.¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 0.96 (3H, t, J=7.0 Hz),1.46–1.58 (11H, m), 1.72–1.85 (2H, m), 2.06–2.25 (1H, m), 3.82 (2H, t,J=6.6 Hz), 4.00 (2H, d, J=6.8 Hz), 4.51 (2H, d, J=4.8 Hz), 4.84 (1H,bs), 7.09–7.13 (2H, m), 8.27 (1H, d, J=9.6 Hz), 8.98 (1H, bs).

(9) A solution oftert-butyl(4-butoxy-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.42 g, 1 mmol), 2-iodoacetamide (0.27 g, 1.5 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.22 mL, 1.5 mmol) inN,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-diisopropyl ether to givetert-butyl[6-(2-amino-2-oxoethoxy)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.37 g, 78.7%) as crystals.

Melting point 180–181° C. Elemental analysis for C₂₅H₃₇N₃O₆ Calculated:C, 63.14; H, 7.84; N, 8.84. Found: C, 62.90; H, 7.71; N, 8.98.¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.3 Hz), 1.46(9H, s), 1.51–1.67 (2H, m), 1.80–1.94 (2H, m), 2.05–2.23 (2H, m), 3.84(2H, t, J=6.6 Hz), 3.98 (2H, d, J=7.2 Hz), 4.51 (2H, d, J=5.6 Hz), 4.62(2H, s), 4.76 (1H, bs), 5.84 (1H, bs), 6.59 (1H, bs), 7.07–7.13 (2H, m),8.37 (1H, d, J=9.2 Hz).

(10) To a solution oftert-butyl[6-(2-amino-2-oxoethoxy)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.29 g, 0.6 mmol) in ethyl acetate (5 mL) was added, a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diisopropyl ether to give2-[[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride (0.23 g, 92.0%) as crystals.

Melting point 248–250° C. Elemental analysis for C₂₀H₃₀N₃O₄Cl 0.5H₂OCalculated: C, 57.07; H, 7.42; N, 9.98. Found: C, 57.22; H, 7.67; N,9.73. ¹H-NMR(DMSO-d₆) δ: 0.87 (6H, d, J=6.6 Hz), 0.99 (3H, t, J=7.3 Hz),1.47 (9H, s), 1.47–1.65 (2H, m), 1.73–2.04 (3H, m), 3.88–3.95 (4H, m),4.17 (2H, s), 4.64 (2H, s), 7.06 (1H, d, J=2.5 Hz), 7.23 (1H, dd, J=2.5,8.8 Hz), 7.46 (1H, s), 7.73 (1H, s), 8.20 (1H, d, J=9.2 Hz), 8.62 (3H,s).

Example 151(E)-3-[3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride

(1) To a solution of ethyl diethylphosphonoacetate (1.4 mL, 7 mmol) inN,N-dimethylformamide (30 mL) was added sodium hydride (0.28 g, 7 mmol)(60% in oil) and the mixture was stirred at room temperature for 10 min.To the obtained mixture was added a solution of tert-butyl(4-butoxy-6-formyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(3.01 g, 7 mmol) in N,N-dimethylformamide (10 mL) and the mixture wasstirred at room temperature for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give ethyl(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-2-propenate(3.11 g, 88.9%) as crystals.

¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.06 (3H, t, J=7.2 Hz), 1.37(3H, t, J=7.2 Hz), 1.47 (9H, s), 1.53–1.68 (2H, m), 1.84–1.94 (2H, m),2.12–2.22 (1H, m), 3.87 (2H, t, J=6.6 Hz), 3.99 (2H, d, J=7.5 Hz), 4.30(2H, q, J=7.2 Hz), 4.52 (2H, d, J=5.7 Hz), 4.78 (1H, bs), 6.58 (1H, d,J=16.0 Hz), 7.65 (1H, dd, J=1.5, 8.1 Hz), 7.79 (1H, d, J=1.5 Hz), 7.79(1H, d, J=16.0 Hz), 8.41 (1H, d, J=8.1 Hz).

(2) To a solution of ethyl(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-2-propenate(1.00 g, 2 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) wasadded 1N sodium hydroxide (4 mL). The obtained mixture was stirred atroom temperature for 2 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-diisopropyl ether to give(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-2-propenicacid (0.89 g, 94.7%) as crystals.

Melting point 207–209° C. Elemental analysis for C₂₆H₃₆N₂O₆ Calculated:C, 66.08; H, 7.68; N, 5.93. Found: C, 65.85; H, 7.52; N, 5.91.¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.07 (3H, t, J=7.3 Hz), 1.49(9H, s), 1.49–1.69 (2H, m), 1.83–1.97 (2H, m), 2.05–2.24 (1H, m), 3.88(2H, t, J=6.4 Hz), 3.99 (2H, d, J=7.2 Hz), 4.53 (2H, d, J=5.6 Hz), 5.16(1H, bs), 6.58 (1H, d, J=16.0 Hz), 7.62 (1H, d, J=8.2 Hz), 7.71 (1H, s),7.84 (1H, d, J=16.0 Hz), 8.36 (1H, d, J=8.2 Hz).

(3) A solution of(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenicacid (0.47 g, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.38 g, 2 mmol) and 1-hydroxybenzotriazole ammonium salt(0.30 g, 2 mmol) in N,N-dimethylformamide (10 mL) was stirred at roomtemperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-n-hexane to give(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide(0.41 g, 87.2%) as crystals.

Melting point 149–150° C. Elemental analysis for C₂₆H₃₇N₃O₅ 0.5H₂OCalculated: C, 64.98; H, 7.97; N, 8.74. Found: C, 64.71; H, 7.68; N,8.56. ¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.01 (3H, t, J=7.4 Hz),1.47 (9H, s), 1.49–1.67 (2H, m), 1.81–1.95 (2H, m), 2.09–2.21 (1H, m),3.86 (2H, t, J=6.5 Hz), 3.99 (2H, d, J=7.2 Hz), 4.52 (2H, d, J=5.6 Hz),4.95 (1H, bs), 5.86 (1H, bs), 6.01 (1H, bs), 6.60 (1H, d, J=16.2 Hz),7.58 (1H, d, J=8.5 Hz), 7.71 (1H, s), 7.74 (1H, d, J=16.2 Hz), 8.33 (1H,d, J=8.4 Hz).

(4) To a solution of(E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide(0.14 g, 0.3 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diisopropyl ether to give(E)-3-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 223–225° C. Elemental analysis for C₂₁H₃₀N₃O₃Cl 0.5H₂OCalculated: C, 60.49; H, 7.49; N, 10.08. Found: C, 60.37; H, 7.77; N,9.73. ¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.01 (3H, t, J=7.2 Hz),1.48–1.66 (2H, m), 1.82–2.08 (3H, m), 3.93–3.99 (4H, m), 4.18 (2H, d,J=4.8 Hz), 6.84 (1H, d, J=16.1 Hz), 7.28 (1H, bs), 7.64 (1H, d, J=16.1Hz), 7.76 (1H, bs), 7.80–7.87 (2H, m), 8.29 (1H, d, J=8.0 Hz), 8.64 (3H,bs).

Example 152(E)-3-[3-(Amninomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide

(1) To a suspension of(E)-3-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride (2.04 g, 5 mmol) in water (20 mL) was added 1N sodiumhydroxide (20 mL). The obtained mixture was stirred at room temperaturefor 10 min. The reaction mixture was poured into water and extractedwith ethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained crystals were recrystallized from ethyl acetate to give(E)-3-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide(1.02 g, 85.0%) as crystals.

Melting point 173–175° C. Elemental analysis for C₂₁H₂₉N₃O₃ Calculated:C, 67.90; H, 7.87; N, 11.31. Found: C, 67.73; H, 7.90; N, 11.03.¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.05 (3H, t, J=7.3 Hz), 1.42(2H, bs), 1.47–1.69 (2H, m), 1.81–1.95 (1H, m), 3.89 (2H, t, J=6.4 Hz),4.01 (2H, s), 4.10 (2H, d, J=7.4 Hz), 5.89 (1H, bs), 6.04 (1H, bs), 6.65(1H, d, J=15.6 Hz), 7.62 (1H, dd, J=1.4, 8.4 Hz), 7.76 (1H, d, J=1.4Hz), 7.78 (1H, d, J=15.6 Hz), 8.39 (1H, d, J=8.4 Hz).

Powder X-ray crystal diffraction data Diffraction angle: 2θ(°)(angstrom) spacing: d value 8.62 10.2 9.98 8.86 17.4 5.09 23.0 3.87 21.94.06 26.3 3.38 24.2 3.68

Example 1533-(Aminomethyl)-4-butoxy-2-isobutyl-6-(1,3-oxazol-5-yl)-1(2H)-isoquinolinonehydrochloride

(1) A solution oftert-butyl(4-butoxy-6-formyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.34 g, 0.8 mmol), p-toluenesulfonylmethyl isocyanide (0.16 g, 0.8mmol) and potassium carbonate (0.22 g, 1.6 mmol) in methanol (10 mL) wasrefluxed under heating for 30 min. The reaction mixture was poured intowater and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography and the precipitated crystals were recrystallized fromethyl acetate-diisopropyl ether to givetert-butyl[4-butoxy-2-isobutyl-6-(1,3-oxazol-5-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]-methylcarbamate(0.34 g, 91.9%) as crystals.

Melting point 152–153° C. Elemental analysis for C₂₆H₃₅N₃O₅ Calculated:C, 66.50; H, 7.51; N, 8.95. Found: C, 66.25; H, 7.57; N, 9.00.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=7.0 Hz), 1.07 (3H, t, J=7.3 Hz), 1.47(9H, s), 1.55–1.73 (2H, m), 1.84–1.98 (2H, m), 2.12–2.26 (1H, m), 3.91(2H, t, J=6.4 Hz), 4.00 (2H, d, J=7.4 Hz), 4.54 (2H, d, J=5.4 Hz), 4.81(1H, bs), 7.53 (1H, d, J=0.8 Hz), 7.72–7.78 (1H, m), 7.97 (1H, s), 8.01(1H, d, J=0.8 Hz), 8.45 (1H, dd, J=1.4, 8.4 Hz).

(2) To a solution oftert-butyl[4-butoxy-2-isobutyl-6-(1,3-oxazol-5-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.28 g, 0.6 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 ml) and the obtained solution wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diisopropyl ether to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1,3-oxazol-5-yl)-1(2H)-isoquinolinonehydrochloride (0.22 g, 91.7%) as crystals.

Melting point 211–213° C. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz),1.03 (3H, t, J=7.3 Hz), 1.55–1.67 (2H, m), 1.84–1.93 (2H, m), 2.02–2.12(1H, m), 3.96–4.01 (4H, m), 4.20 (2H, d, J=5.4 Hz), 8.00–8.02 (3H, m),8.36 (1H, d, J=9.0 Hz), 8.64 (1H, s), 8.82 (3H, bs).

Example 1542-[[3-(Aminomethyl)-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamide

(1) To a suspension of 4-benzyloxyphthalic anhydride (25.42 g, 100 mmol)in methanol (200 mL) was added 28% sodium methoxide methanol solution(21.22 g, 110 mmol) and the mixture was stirred at room temperature for1 h. The reaction mixture was poured into 1N hydrochloric acid (150 mL)and extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (200 mL)and methyl 2-(isobutylamino)acetate (17.42 g, 120 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.00 g,120 mmol) and 1-hydroxybenzotriazole (18.34 g, 120 mmol) were added, andthe mixture was stirred at room temperature for 3 h. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was dissolved inmethanol (50 mL) and a solution of 28% sodium methoxide methanolsolution (38.59 g, 200 mmol) was added thereto. The mixture was stirredat room temperature for 1 h. The reaction mixture was poured into 1Nhydrochloric acid (200 mL) and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography and the component eluted earlier wasconcentrated to give methyl7-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(4.76 g, 12.1%) as an oil.

¹H-NMR(CDCl₃) δ: 0.82 (6H, d, J=6.6 Hz), 1.78–1.87 (1H, m), 3.99 (3H,s), 4.39 (2H, d, J=7.5 Hz), 5.25 (2H, s), 7.25–7.48 (6H, m), 7.96–7.98(1H, m), 8.10 (1H, d, J=8.7 Hz), 11.34 (1H, s).

The component eluted later was concentrated to give methyl6-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(21.41 g, 54.4%) as crystals.

Melting point 109–110° C. Elemental analysis for C₂₂H₂₃NO₅ Calculated:C, 69.28; H, 6.08; N, 3.67. Found: C, 69.28; H, 5.93; N, 3.48.¹H-NMR(CDCl₃) δ: 0.81 (6H, d, J=6.6 Hz), 1.66–1.85 (1H, m), 4.00 (3H,s), 4.35 (2H, d, J=7.5 Hz), 5.21 (2H, s), 7.31 (1H, dd, J=2.6, 8.8 Hz),7.38–7.49 (5H, m), 7.60 (1H, d, J=2.6 Hz), 8.38 (1H, d, J=8.8 Hz), 11.12(1H, s).

(2) To a solution of methyl6-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(7.86 g, 20 mmol) in N,N-dimethylformamide (100 mL) was added sodiumhydride (0.96 g, 24 mmol) (60% in oil) at 0° C. and the mixture wasstirred at 0° C. for 30 min. To the obtained mixture was addedN-phenyltrifluoromethanesulfonimide (8.57 g, 24 mmol) and the mixturewas stirred at room temperature for 3 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. After washing the extractwith water, the extract was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give methyl6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(10.50 g, 100%) as an oil.

¹H-NMR(CDCl₃) δ: 0.88 (6H, d, J=7.0 Hz), 1.92–2.05 (1H, m), 3.99 (3H,s), 5.19 (2H, s), 7.23–7.48 (2H, m), 8.37 (1H, d, J=9.2 Hz).

(3) A mixture of methyl6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(10.50 g, 20 mmol), 2-fluorophenylboronic acid (3.36 g, 24 mmol) andsodium carbonate (5.30 g, 50 mmol) in toluene (50 mL), ethanol (10 mL)and water (10 mL) was stirred under an argon atmosphere at roomtemperature for 30 min. To the obtained mixture was addedtetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) and the mixturewas refluxed under heating under an argon atmosphere for 12 h. Thereaction mixture was poured into water and extracted with ethyl acetate.After washing the extract with water, the extract was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give methyl6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(6.06 g, 65.9%) as crystals.

Melting point 106–107° C. Elemental analysis for C₂₈H₂₆NO₄F Calculated:C, 73.19; H, 5.70; N, 3.05. Found: C, 73.18; H, 5.83; N, 2.86.¹H-NMR(CDCl₃) δ: 0.91 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=7.0 Hz),2.05–2.19 (1H, m), 3.47 (3H, s), 3.86 (1H, dd, J=7.6, 13.8 Hz), 4.08(1H, dd, J=7.6, 13.8 Hz), 4.98 (2H, s), 6.50–6.52 (1H, m), 7.13–7.50(10H, m), 8.43 (1H, d, J=8.8 Hz).

(4) To a solution of methyl6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(0.46 g, 1 mmol) in methanol (30 mL) was added an aqueous solution (3mL) of lithium hydroxide monohydrate (0.42 g, 10 mmol). The obtainedmixture was refluxed under heating for 12 h. The reaction mixture waspoured into water, acidified with 1N hydrochloric acid and extractedwith ethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained crystals were recrystallized from ethyl acetate-diisopropylether to give6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (0.41 g, 93.2%) as crystals.

Melting point 178–179° C. Elemental analysis for C₂₇H₂₄NO₄F 0.25H₂OCalculated: C, 72.07; H, 5.49; N, 3.11. Found: C, 72.28; H, 5.20; N,2.80. ¹H-NMR(CDCl₃) δ: 0.85 (6H, d, J=6.8 Hz), 2.09–2.23 (1H, m),3.75–3.96 (2H, m), 4.38 (1H, bs), 4.98 (2H, s), 6.49–6.51 (1H, m),7.10–7.48 (10H, m), 8.30 (1H, d, J=8.8 Hz).

(5) To a solution of6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (4.90 g, 11 mmol) in tetrahydrofuran (50 mL) were added oxalylchloride (1.1 mL, 13.2 mmol) and N,N-dimethylformamide (3 drops), andthe mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (30 mL). The obtained solution was addeddropwise to a suspension of sodium tetrahydroborate (1.46 g, 38.5 mmol)in 1,2-dimethoxyethane (30 mL) at 0° C. The obtained mixture was stirredat 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloricacid and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give6-benzyloxy-4-(2-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(4.38 g, 92.4%) as crystals.

Melting point 191–192° C. Elemental analysis for C₂₇H₂₆NO₃F 0.25H₂OCalculated: C, 74.38; H, 6.13; N, 3.21. Found: C, 74.52; H, 6.20; N,3.16. ¹H-NMR(CDCl₃) δ: 0.87 (6H, d, J=6.6 Hz), 1.85 (1H, bs), 2.18–2.32(1H, m), 4.08–4.29 (2H, m), 4.44 (2H, s), 4.94 (2H, s), 6.38 (1H, d,J=2.3 Hz), 7.09 (1H, dd, J=2.3, 8.6 Hz), 7.18–7.36 (7H, m), 7.43–7.54(1H, m), 8.36 (1H, d, J=8.6 Hz).

(6) To a suspension of6-benzyloxy-4-(2-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(4.31 g, 10 mmol) in toluene (50 mL) was added thionyl chloride (1.5 mL,20 mmol). The obtained mixture was refluxed under heating for 2 h. Thereaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-benzyloxy-3-chloromethyl-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(4.29 g, 95.3%) as crystals.

¹H-NMR(CDCl₃) δ: 0.98 (3H, d, J=6.6 Hz), 1.01 (3H, d, J=6.8 Hz),2.15–2.26 (1H, m), 3.94 (1H, dd, J=7.9, 13.1 Hz), 4.31 (1H, d, J=12.4Hz), 4.35 (1H, dd, J=7.9, 13.1 Hz), 4.43 (1H, d, J=12.4 Hz), 4.95 (2H,s), 6.36–6.38 (1H, m), 7.12–7.35 (9H, m), 7.45–7.56 (1H, m), 8.41 (1H,d, J=8.8 Hz).

(7) A solution of6-benzyloxy-3-chloromethyl-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(4.27 g, 9.5 mmol) and potassium phthalimide (2.65 g, 14.3 mmol) inN,N-dimethylformamide (100 mL) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give2-[[6-benzyloxy-4-(2fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(5.07 g, 95.3%) as an amorphous.

¹H-NMR(CDCl₃) δ: 1.00 (3H, d, J=6.6 Hz), 1.01 (3H, d, J=6.8 Hz),2.12–2.27 (1H, m), 3.94 (1H, dd, J=7.3, 14.8 Hz), 4.33 (1H, dd, J=7.3,13.9 Hz), 4.57 (1H, d, J=15.6 Hz), 4.92 (1H, d, J=15.6 Hz), 4.93 (2H,s), 6.34 (1H, d, J=2.6 Hz), 7.01–7.45 (10H, m), 7.66–7.76 (4H, m), 8.40(1H, d, J=8.8 Hz).

(8) To a solution of2-[[6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(5.05 g, 9 mmol) in ethanol (50 mL) was added hydrazine monohydrate (1.3mL, 27 mmol). The obtained mixture was refluxed under heating for 2 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (50 mL) and di-t-butyl dicarbonate (3.1 mL, 13.5 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-n-hexane to givetert-butyl[6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(4.27 g, 89.5%) as crystals.

Melting point 138–139° C. Elemental analysis for C₃₂H₃₅N₂O₄F Calculated:C, 72.43; H, 6.65; N, 5.28. Found: C, 72.27; H, 6.38; N, 5.22.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.16–2.30 (1H,m), 3.83–3.94 (1H, m), 3.99–4.38 (3H, m), 4.58 (1H, bs), 4.95 (2H, s),6.33 (1H, d, J=2.4 Hz), 7.11 (1H, dd, J=2.4, 9.0 Hz), 7.16–7.38 (8H, m),7.43–7.54 (1H, m), 8.39 (1H, d, J=9.0 Hz).

(9) A suspension oftert-butyl[6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(3.98 g, 7.5 mmol) and 5% palladium carbon (1.5 g) in ethanol (50 mL)was stirred under a hydrogen atmosphere at room temperatures for 2 h.The catalyst was filtered off and the filtrate was concentrated underreduced pressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to givetert-butyl[4-(2-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(3.11 g, 94.2%) as crystals.

Melting point 163–164° C. Elemental analysis for C₂₅H₂₉N₂O₄F 0.5H₂OCalculated: C, 66.80; H, 6.73; N, 6.23. Found: C, 66.80; H, 6.93; N,6.28. ¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.11–2.28(1H, m), 3.82–3.92 (1H, m), 4.02–4.21 (2H, m), 4.28–4.38 (1H, m), 4.60(1H, bs), 6.37 (1H, d, J=2.2 Hz), 7.08 (1H, dd, J=2.2, 8.8 Hz),7.13–7.23 (4H, m), 7.34–7.47 (1H, m), 8.28 (1H, d, J=8.8 Hz).

(10) A solution oftert-butyl[4-(2-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.44 g, 1 mmol), 2-iodoacetamide (0.37 g, 2 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.30 mL, 2 mmol) inN,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[6-(2-amino-2-oxoethoxy)-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.30 g, 61.2%) as crystals.

Melting point 186–188° C. Elemental analysis for C₂₇H₃₂N₃O₅F 0.25H₂OCalculated: C, 64.59; H, 6.52; N, 8.37. Found: C, 64.74; H, 6.32; N,7.97. ¹H-NMR(CDCl₃) δ: 0.99 (3H, d, J=7.0 Hz), 1.00 (3H, d, J=6.8 Hz),1.43 (9H, s), 2.15–2.32 (1H, m), 3.85–4.00 (4H, m), 4.35 (2H, s), 4.59(1H, bs), 5.70 (1H, bs), 6.29 (1H, d, J=2.4 Hz), 6.50 (1H, bs), 7.07(1H, dd, J=2.4, 9.0 Hz), 7.21–7.37 (3H, m), 7.46–7.58 (1H, m), 8.44 (1H,d, J=9.0 Hz).

(11) To a solution oftert-butyl[6-(2-amino-2-oxoethyl)-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.25 g, 0.5 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL), and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure. The residue was poured intosaturated aqueous sodium hydrogencarbonate solution and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give2-[[3-(aminomethyl)-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamide(0.02 g, 10.0%) as an amorphous.

¹H-NMR(CDCl₃) δ: 1.00 (3H, d, J=6.6 Hz), 1.02 (3H, d, J=6.6 Hz), 1.66(2H, bs), 2.18–2.32 (1H, m), 4.07–4.28 (3H, m), 4.35 (2H, s), 5.77 (1H,bs), 6.27 (1H, d, J=2.6 Hz), 6.51 (1H, bs), 7.05 (1H, dd, J=2.6, 8.8Hz), 7.22–7.35 (3H, m), 7.45–7.56 (1H, m), 8.44 (1H, d, J=8.8 Hz).

Example 1553-(Aminomethyl)-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

(1) To a solution oftert-butyl[4-(2-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(Example 8(9)) (2.42 g, 5.5 mmol) in N,N-dimethylformamide (30 mL) wasadded sodium hydride (0.33 g, 8.3 mmol) (60% in oil) at 0° C. and themixture was stirred at 0° C. for 30 min. To the obtained mixture wasadded N-phenyltrifluoromethanesulfonimide (2.97 g, 8.3 mmol) and themixture was stirred at room temperature for 1 h. The reaction mixturewas poured into water and extracted with ethyl acetate. After washingthe extract with water, the extract was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[4-(2-fluorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.91 g, 92.4%) as an amorphous.

¹H-NMR(CDCl₃) δ: 1.00 (3H, d, J=6.6 Hz), 1.01 (3H, d, J=7.0 Hz), 1.46(9H, s), 2.17–2.31 (1H, m), 3.89–3.99 (1H, m), 4.07–4.27 (2H, m),4.33–4.44 (1H, m), 4.59 (1H, bs), 6.79 (1H, d, J=2.2 Hz), 7.21–7.44 (1H,m), 7.48–7.60 (1H, m), 8.57 (1H, d, J=8.8 Hz).

(2) A mixed solution oftert-butyl[4-(2-fluorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.86 g, 5 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.14 g, 0.25mmol), triethylamine (0.77 mL, 5.5 mmol) and palladium acetate (56 mg,0.25 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was stirredwith heating at 100° C. under a carbon monoxide atmosphere at 5 atm for1 h. The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give methyl3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(2.23 g, 92.5%) as crystals.

Melting point 180–181° C. Elemental analysis for C₂₇H₃₁N₂O₅F Calculated:C, 67.20; H, 6.48; N, 5.81. Found: C, 66.95; H, 6.55; N, 5.75.¹H-NMR(CDCl₃) δ: 1.00 (3H, d, J=6.6 Hz), 1.01 (3H, d, J=6.6 Hz), 1.43(9H, s), 2.19–2.33 (1H, m), 3.86 (3H, s), 3.89–4.43 (4H, m), 4.62 (1H,bs), 7.23–7.38 (3H, m), 7.47–7.58 (1H, m), 7.46 (1H, d, J=1.5 Hz), 8.06(1H, dd, J=1.5, 8.4 Hz), 8.53 (1H, d, J=8.4 Hz).

(3) To a solution of methyl3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(1.93 g, 4 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) wasadded 1N sodium hydroxide (8 mL). The obtained mixture was stirred atroom temperature for 1 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-isopropyl ether to give3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (1.77 g, 94.7%) as crystals.

Melting point 213–214° C. Elemental analysis for C₂₆H₂₉N₂O₅F Calculated:C, 66.65; H, 6.24; N, 5.98. Found: C, 66.51; H, 6.50; N, 5.99.¹H-NMR(CDCl₃) δ: 1.00 (3H, d, J=6.8 Hz), 1.01 (3H, d, J=6.6 Hz), 1.45(9H, s), 2.19–2.32 (1H, m), 4.84 (1H, bs), 7.22–7.34 (3H, m), 7.46–7.57(1H, m), 7.65 (1H, s), 8.05 (1H, d, J=8.4 Hz), 8.51 (1H, d, J=8.4 Hz).

(4) A solution of3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (0.70 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt(0.46 g, 3 mmol) in N,N-dimethylformamide (10 mL) was stirred at roomtemperature for 3 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(0.67 g, 95.7%) as crystals.

Melting point 232–233° C. Elemental analysis for C₂₆H₃₀N₃O₄F Calculated:C, 66.79; H, 6.47; N, 8.99. Found: C, 66.39; H, 6.75; N, 8.93.¹H-NMR(CDCl₃) δ: 0.99 (3H, d, J=6.6 Hz), 1.01 (3H, d, J=6.6 Hz), 1.44(9H, s), 2.22–2.30 (1H, m), 3.92–4.19 (3H, m), 4.32–4.40 (1H, m), 4.69(1H, bs), 5.78 (1H, bs), 6.10 (1H, bs), 7.23–7.35 (3H, m), 7.40 (1H, d,J=1.5 Hz), 7.47–7.54 (1H, m), 7.77 (1H, dd, J=1.5, 8.4 Hz), 8.49 (1H, d,J=8.4 Hz).

(5) To a solution of3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(0.37 g, 0.8 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 ml) and the obtained solution wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diethyl ether to give3-(aminomethyl)-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride (0.30 g, 93.8%) as crystals.

Melting point 216–218° C. Elemental analysis for C₂₁H₂₃N₃O₂ClF 2H₂OCalculated: C, 57.34; H, 6.19; N, 9.55. Found: C, 57.41; H, 5.93; N,9.71. ¹H-NMR(DMSO-d₆) δ: 0.92 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz),2.01–2.16 (1H, m), 3.62–3.80 (1H, m), 4.02–4.23 (3H, m), 7.43–7.66 (6H,m), 8.03 (1H, d, J=8.4 Hz), 8.21 (1H, bs), 8.38 (1H, d, J=8.4 Hz), 8.72(3H, bs).

Example 1563-(Aminomethyl)-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carbonitrilehydrochloride

(1) A solution of3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(Example 10 (4)) (0.23 g, 0.5 mmol) and cyanuric chloride (0.28 g, 1.5mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas recrystallized from ethyl acetate-n-hexane to givetert-butyl[6-cyano-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.19 g, 86.4%) as crystals.

Melting point 191–192° C. Elemental analysis for C₂₆H₂₈N₃O₃F Calculated:C, 69.47; H, 6.28; N, 9.35. Found: C, 69.37; H, 6.42; N, 9.24.¹H-NMR(CDCl₃) δ: 1.00 (3H, d, J=6.6 Hz), 1.01 (3H, d, J=7.0 Hz), 1.43(9H, s), 2.18–2.32 (1H, m), 3.89–4.05 (1H, m), 4.07–4.44 (3H, m), 4.58(1H, bs), 7.20–7.40 (4H, m), 7.50–7.61 (1H, m), 7.67 (1H, dd, J=1.6, 8.2Hz), 8.56 (1H, d, J=8.2 Hz).

(2) To a solution oftert-butyl[6-cyano-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.13 g, 0.3 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diethyl ether to give3-(aminomethyl)-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carbonitrilehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 228–230° C. ¹H-NMR(DMSO-d₆) δ: 0.92 (3H, d, J=6.6 Hz),0.94 (3H, d, J=6.6 Hz), 1.99–2.19 (1H, m), 3.76–3.83 (1H, m), 3.96–4.22(3H, m), 7.30 (1H, d, J=1.4 Hz), 7.41–7.72 (4H, m), 7.99 (1H, dd, J=1.4,8.4 Hz), 8.49 (1H, d, J=8.4 Hz), 8.74 (3H, bs).

Example 1572-[[3-(Aminomethyl)-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride

(1) A mixture of methyl6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(10.26 g, 20 mmol), 3-fluorophenylboronic acid (3.36 g, 24 mmol) andsodium carbonate (5.30 g, 50 mmol) in toluene (50 mL), ethanol (10 mL)and water (10 mL) was stirred under an argon atmosphere at roomtemperature for 30 min. To the obtained mixture was addedtetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) and the mixturewas refluxed under heating under an argon atmosphere for 12 h. Thereaction mixture was poured into water and extracted with ethyl acetate.After washing the extract with water, the extract was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give methyl6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(6.31 g, 68.7%) as crystals.

Melting point 127–128° C. Elemental analysis for C₂₈H₂₆NO₄F Calculated:C, 73.19; H, 5.70; N, 3.05. Found: C, 73.03; H, 5.63; N, 2.77.¹H-NMR(CDCl₃) δ: 0.91 (6H, d, J=7.0 Hz), 2.04–2.19 (1H, m), 3.50 (3H,s), 3.8–4.00 (2H, m), 4.99 (2H, s), 6.57 (1H, d, J=2.4 Hz), 6.96–7.21(4H, m), 7.24–7.46 (6H, m), 8.43 (1H, d, J=8.8 Hz).

(2) To a solution of methyl6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(5.97 g, 13 mmol) in tetrahydrofuran (50 mL) and methanol (50 mL) wasadded an aqueous solution (10 mL) of lithium hydroxide monohydrate (1.64g, 39 mmol). The obtained mixture was refluxed under heating for 12 h.The reaction mixture was poured into water, acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (50 mL), and oxalyl chloride (1.0 mL, 12 mmol) andN,N-dimethylformamide (3 drops) were added thereto. The mixture wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved intetrahydrofuran (30 mL). The obtained solution was added dropwise to asuspension of sodium tetrahydroborate (1.32 g, 35 mmol) in1,2-dimethoxyethane (30 mL) at 0° C. The obtained mixture was stirred at0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give6-benzyloxy-4-(3-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(1.39 g, 32.2%) as crystals.

Melting point 146–146.5° C. Elemental analysis for C₂₇H₂₆NO₃FCalculated: C, 75.15; H, 6.07; N, 3.25. Found: C, 74.87; H, 6.06; N,3.12. ¹H-NMR(CDCl₃) δ: 0.94 (6H, d, J=6.6 Hz), 2.11–2.28 (1H, m), 2.58(1H, bs), 4.16 (2H, d, J=7.6 Hz), 4.41 (2H, d, J=5.8 Hz), 4.91 (2H, s),6.31 (1H, d, J=2.2 Hz), 6.95–7.37 (9H, m), 7.44–7.52 (1H, m), 8.25 (1H,d, J=8.8 Hz).

(3) To a suspension of6-benzyloxy-4-(3-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(3.88 g, 9 mmol) in toluene (30 mL) was added thionyl chloride (1.3 mL,18 mmol). The obtained mixture was refluxed under heating for 2 h. Thereaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-benzyloxy-3-chloromethyl-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(3.71 g, 91.8%) as an oil.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.13–2.31 (1H, m), 4.14 (2H, d,J=7.2 Hz), 4.35 (2H, s), 4.96 (2H, s), 6.37 (1H, d, J=2.2 Hz), 6.98–7.32(9H, m), 7.42–7.53 (1H, m), 8.40 (1H, d, J=8.8 Hz).

(4) A solution of6-benzyloxy-3-chloromethyl-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(3.60 g, 8 mmol) and potassium phthalimide (2.22 g, 12 mmol) inN,N-dimethylformamide (30 ml) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give2-[[6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(3.95 g, 88.2%) as crystals.

¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.10–2.27 (1H, m), 4.03 (2H, d,J=4.4 Hz), 4.75 (2H, s), 4.92 (2H, s), 6.32 (1H, d, J=2.6 Hz), 6.98–7.14(4H, m), 7.21–7.40 (6H, m), 7.68–7.78 (4H, m), 8.38 (1H, d, J=8.8 Hz).

(5) To a solution of2-[[6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(3.92 g, 7 mmol) in ethanol (50 mL) was added hydrazine monohydrate (1.0mL, 21 mmol). The obtained mixture was refluxed under heating for 2 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL) and di-t-butyl dicarbonate (2.4 mL, 10.5 mol)was added. The obtained mixture was stirred at room temperature for 1 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl[(6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(3.47 g, 93.5%) as crystals.

Melting point 180–181° C. Elemental analysis for C₃₂H₃₅N₂O₄F Calculated:C, 72.43; H, 6.65; N, 5.28. Found: C, 72.30; H, 6.48; N, 5.32.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.15–2.28 (1H,m), 4.02 (2H, d, J=7.4 Hz), 4.16 (2H, d, J=5.0 Hz), 4.94 (2H, s), 6.31(1H, d, J=2.6 Hz), 6.89–7.35 (9H, m), 7.41–7.52 (1H, m), 8.36 (1H, d,J=8.8 Hz).

(6) A suspension oftert-butyl[6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(3.18 g, 6 mmol) and 5% palladium carbon (1.0 g) in tetrahydrofuran (20mL) and ethanol (20 mL) was stirred, under a hydrogen atmosphere at roomtemperature for 2 h. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The obtained crystals wererecrystallized from ethyl acetate-n-hexane to givetert-butyl[4-(3-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.54 g, 96.2%) as crystals.

Melting point 161–163° C. Elemental analysis for C₂₅H₂₉N₂O₄F Calculated:C, 68.16; H, 6.64; N, 6.36. Found: C, 67.91; H, 6.89; N, 6.38.¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.14–2.24 (1H,m), 4.01 (2H, d, J=5.7 Hz), 4.18 (2H, d, J=4.5 Hz), 4.52 (1H, bs), 6.34(1H, d, J=2.1 Hz), 6.94–7.13 (4H, m), 7.38–7.46 (1H, m), 7.87 (1H, bs),8.26 (1H, d, J=8.4 Hz).

(7) A solution oftert-butyl[(4-(3-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.44 g, 1 mmol), 2-iodoacetamide (0.37 g, 2 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.3 mL, 2 mmol) inN,N-dimethylacetamide (10 mL) was stirred at 70° C. for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[6-(2-amino-2-oxoethoxy)-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.21 g, 42.9%) as crystals.

Melting point 241–242° C. Elemental analysis for C₂₇H₃₂N₃O₅F 0.25H₂OCalculated: C, 64.59; H, 6.52; N, 8.37. Found: C, 64.61; H, 6.66; N,8.07. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.19–2.34(1H, m), 4.04 (2H, d, J=7.0 Hz), 4.35 (2H, s), 4.86 (1H, bs), 6.15 (1H,bs), 6.31 (1H, d, J=2.6 Hz), 6.59 (1H, bs), 6.99–7.25 (4H, m), 7.45–7.54(1H, m), 8.42 (1H, d, J=9.2 Hz).

(8) To a solution oftert-butyl[6-(2-amino-2-oxoethoxy)-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.15 g, 0.3 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL), and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and crystallized from ethylacetate-diisopropyl ether to give2-[[3-(aminomethyl)-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride (0.12 g, 92.3%) as crystals.

Melting point 209–210° C. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz),1.99–2.18 (1H, m), 3.84 (2H, bs), 3.94–4.08 (2H, m), 4.39 (2H, s), 6.29(1H, d, J=2.2 Hz), 7.18–7.41 (5H, m), 8.27 (1H, d, J=9.2 Hz), 8.59 (3H,bs).

Example 1583-(Aminomethyl)-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

(1) To a solution oftert-butyl[4-(3-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(Example 11 (6)) (1.76 g, 4 mol) in N,N-dimethylformamide (20 mL) wasadded sodium hydride (0.19 g, 4.8 mmol)(60% in oil) at 0° C. and themixture was stirred at 0° C. for 30 min. To the obtained mixture wasadded N-phenyltrifluoromethanesulfonimide (1.71 g, 4.8 mmol) and themixture was stirred at room temperature, for 2 h. The reaction mixturewas poured into water and extracted with ethyl acetate. After washingthe extract with water, the extract was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[4-(3-fluorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.30 g, 100%) as an oil.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.14–2.28 (1H,m), 4.08 (2H, d, J=9.0 Hz), 4.23 (2H, d, J=5.6 Hz), 4.50 (1H, bs), 6.80(1H, d, J=2.6 Hz), 6.96–7.08 (2H, m), 7.18–7.59 (3H, m), 8.55 (1H, d,J=8.8 Hz).

(2) A mixed solution oftert-butyl[4-(3-fluorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.29 g, 4 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.11 g, 0.2mmol), triethylamine (0.6 mL, 4.4 mmol) and palladium acetate (45 mg,0.2 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was stirredwith heating at 100° C. under a carbon monoxide atmosphere at 5 atm for1 h. The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give methyl3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(1.76 g, 91.2%) as crystals.

Melting point 206–208° C. Elemental analysis for C₂₇H₃₁N₂O₅F Calculated:C, 67.20; H, 6.48; N, 5.81. Found: C, 66.96; H, 6.63; N, 5.59.¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.18–2.30 (1H,m), 3.87 (3H, s), 4.08 (2H, d, J=7.2 Hz), 4.21 (2H, d, J=5.1 Hz), 4.54(1H, bs), 6.99–7.08 (2H, m), 7.18–7.27 (1H, m), 7.62 (1H, d, J=1.2 Hz),8.04 (1H, dd, J=1.2, 8.4 Hz), 8.50 (1H, d, J=8.4 Hz).

(3) To a solution of methyl3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(1.45 g, 3 mmol) in tetrahydrofuran (10 mL) and methanol (10 ml) wasadded 1N sodium hydroxide (6 mL). The obtained mixture was stirred atroom temperature for 2 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wascrystallized from ethyl acetate-n-hexane to give3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (1.34 g, 95.7%) as crystals.

Melting point 206–207° C. Elemental analysis for C₂₆H₂₉N₂O₅F Calculated:C, 66.65; H, 6.24; N, 5.98. Found: C, 66.39; H, 6.33; N, 5.63.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.48 (9H, s), 2.10–2.29 (1H,m), 4.05 (2H, d, J=7.4 Hz), 4.17 (2H, d, J=4.4 Hz), 5.49 (1H, bs),7.05–7.27 (3H, m), 7.44–7.58 (2H, m), 7.86–7.90 (1H, m), 8.36 (1H, d,J=8.4 Hz).

(4) A solution of3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (1.17 g, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.96 g, 5 mol) and 1-hydroxybenzotriazole ammonium salt(0.76 g, 5 mmol) in N,N-dimethylformamide (10 mL) was stirred at roomtemperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(0.81 g, 69.8%) as crystals.

Melting point 147–149° C. Elemental analysis for C₂₆H₃₀N₃O₄F 0.5H₂OCalculated: C, 65.53; H, 6.56; N, 8.82. Found: C, 65.91; H, 6.44; N,8.87. ¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.44 (9H, s), 2.14–2.30(1H, m), 4.07 (2H, d, J=7.4 Hz), 4.19 (2H, d, J=5.6 Hz), 4.73 (1H, bs),5.77 (1H, bs), 6.11 (1H, bs), 6.98–7.25 (3H, m), 7.37 (1H, d, J=1.8 Hz),7.45–7.56 (1H, m), 7.72 (1H, dd, J=1.8, 8.4 Hz), 8.42 (1H, d, J=8.4 Hz).

(5) To a solution of3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(0.28 g, 0.6 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diethyl ether to give3-(aminomethyl)-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride (0.22 g, 91.7%) as crystals.

Melting point 292–293° C. Elemental analysis for C₂₁H₂₃N₃O₂ClF 0.5H₂OCalculated: C, 61.09; H, 5.86; N, 10.18. Found: C, 60.79; H, 6.09; N,10.04. ¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.02–2.19 (1H, m),3.87 (2H, bs), 4.00–4.20 (2H, m), 7.26–7.45 (4H, m), 7.58–7.69 (2H, m),8.01 (1H, dd, J=1.6, 8.4 Hz), 8.19 (1H, bs), 8.38 (1H, d, J=8.4 Hz),8.61 (3H, bs).

Example 159(E)-3-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride

(1) To a solution of3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxylicacid (6.31 g, 14 mmol) and N-methylmorpholine (1.8 mL, 16.8 mmol) intetrahydrofuran (50 mL) was added ethyl chloroformate (1.6 mL, 16.8mmol) at 0° C. and the mixture was stirred at 0° C. for 10 min. To theobtained mixture were added sodium tetrahydroborate (1.59 g, 42 mmol)and methanol (5 mL) and the mixture was stirred at 0° C. for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The precipitatedcrystals were recrystallized from ethyl acetate-diisopropyl ether togivetert-butyl(6-hydroxymethyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(4.73 g, 77.4%) as crystals.

Melting point 169–170° C. Elemental analysis for C₂₆H₃₂N₂O₄ Calculated:C, 71.53; H, 7.39; N, 6.42. Found: C, 71.25; H, 7.49; N, 6.35.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.04 (1H, bs),2.16–2.29 (1H, m), 4.06 (2H, d, J=7.4 Hz), 4.18 (2H, d, J=5.4 Hz), 4.64(2H, d, J=6.0 Hz), 4.66 (1H, bs), 6.89 (1H, s), 7.22–7.27 (2H, m),7.49–7.54 (4H, m), 8.38 (1H, d, J=8.0 Hz).

(2) To a solution oftert-butyl(6-hydroxymethyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(4.58 g, 10.5 mmol) in tetrahydrofuran (50 mL) was added manganesedioxide (13.7 g) and the mixture was stirred at room temperature for 12h. Manganese dioxide was filtered off and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to givetert-butyl(6-formyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(4.12 g, 90.4%) as crystals.

Melting point 183–184° C. Elemental analysis for C₂₆H₃₀N₂O₄ Calculated:C, 71.87; H, 6.96; N, 6.45. Found: C, 71.79; H, 6.84; N, 6.36.¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.19–2.32 (1H,m), 4.10 (2H, d, J=7.4 Hz), 4.24 (2H, d, J=5.6 Hz), 4.51 (1H, bs),7.26–7.30 (2H, m), 7.44 (1H, d, J=1.4 Hz), 7.51–7.59 (3H, m), 7.92 (1H,dd, J=1.4, 8.2 Hz), 8.59 (1H, d, J=8.2 Hz), 9.95 (1H, s).

(3) To a solution of ethyl diethylphosphonoacetate (1.0 mL, 5 mmol) inN,N-dimethylformamide (20 mL) was added sodium hydride (0.20 g, 5 mmol)(60% in oil), and the mixture was stirred at room temperature for 10min. To the obtained mixture was added a solution of tert-butyl(6-formyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(2.17 g, 5 mmol) in N,N-dimethylformamide (20 mL) and the mixture wasstirred at room temperature for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give ethyl(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenate(2.03 g, 71.7%) as an amorphous.

Melting point 147–148° C. Elemental analysis for C₃₀H₃₆N₂O₅ Calculated:C, 71.40; H, 7.19; N, 5.55. Found: C, 71.37; H, 7.15; N, 5.43.¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=7.0 Hz), 1.31 (3H, t, J=7.3 Hz), 1.43(9H, s), 2.18–2.31 (1H, m), 4.08 (2H, d, J=7.4 Hz), 4.13–4.28 (4H, m),4.53 (1H, bs), 6.37 (1H, d, J=16.2 Hz), 7.00 (1H, d, J=1.4 Hz),7.18–7.28 (2H, m), 7.44–7.67 (5H, m), 8.44 (1H, d, J=8.0 Hz).

(4) To a solution of ethyl(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenate(0.70 g, 1.4 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) wasadded 1N sodium hydroxide (3 mL). The obtained mixture was stirred atroom temperature for 1 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-n-hexane to give(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.56 g, 84.8%) as crystals.

Melting point 172–173° C. Elemental analysis for C₂₈H₃₂N₂O₅ Calculated:C, 70.27; H, 7.16; N, 5.85. Found: C, 70.08; H, 6.80; N, 5.65.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.48 (9H, s), 2.16–2.24 (1H,m), 4.06 (2H, d, J=7.2 Hz), 4.15 (2H, d, J=4.0 Hz), 5.62 (1H, bs), 6.27(1H, d, J=16.0 Hz), 6.82 (1H, s), 7.33–7.40 (3H, m), 7.48–7.58 (3H, m),8.28 (1H, d, J=8.8 Hz).

(5) A solution of(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.33 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammoniumsalt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 mL) was stirred atroom temperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.31 g, 93.9%) as crystals.

Melting point 146–147° C. Elemental analysis for C₂₈H₃₃N₃O₄ 0.25H₂OCalculated: C, 70.05; H, 7.03; N, 8.75. Found: C, 70.08; H, 7.09; N,8.64. ¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.16–2.24(1H, m), 4.07 (2H, d, J=7.4 Hz), 4.19 (2H, d, J=5.6 Hz), 4.96 (1H, bs),5.75 (1H, bs), 6.38 (1H, d, J=15.6 Hz), 6.94 (1H, s), 7.26–7.30 (2H, m),7.40–7.56 (5H, m), 8.29 (1H, d, J=8.4 Hz).

(6) A solution of(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.24 g, 0.5 mmol) in ethyl acetate, (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL), and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diisopropyl ether to give(E)-3-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride (0.20 g, 95.2%) as crystals.

Melting point 223–225° C. Elemental analysis for C₂₃H₂₆N₃O₂Cl 1.5H₂OCalculated: C, 62.93; H, 6.66; N, 9.57. Found: C, 63.15; H, 6.66; N,9.34. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.9 Hz), 2.06–2.16 (1H, m), 3.87(2H, d, J=4.8 Hz), 4.08 (2H, s), 6.56 (1H, d, J=16.0 Hz), 7.19 (1H, bs),7.31 (1H, d, J=16.0 Hz), 7.42–7.44 (2H, m), 7.54–7.63 (3H, m), 7.69 (1H,bs), 7.78 (1H, dd, J=1.2, 8.8 Hz), 8.35 (1H, d, J=8.8 Hz), 8.62 (3H,bs).

Example 160(E)-3-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamide

(1)(E)-3-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride (Example 159 (6)) (0.13 g, 0.3 mmol) was dissolved inwater (10 mL) and saturated aqueous potassium carbonate solution (10 mL)was added. The mixture was extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The precipitated crystals wererecrystallized from ethyl acetate-diisopropyl ether to give(E)-3-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.06 g, 54.5%) as crystals.

Melting point 228–230° C. ¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.47(2H, bs), 2.19–2.33 (1H, m), 3.69 (2H, s), 4.22 (2H, d, J=7.0 Hz), 5.70(2H, bs), 6.43 (1H, d, J=15.8 Hz), 6.99 (1H, d, J=1.5 Hz), 7.25–7.29(2H, m), 7.47–7.55 (4H, m), 7.58 (1H, dd, J=1.5, 8.4 Hz), 8.44 (1H, d,J=8.4 Hz).

Recrystallization from ethanol-ethyl acetate gave crystals in adifferent crystal form.

Melting point 275–276° C.

Powder X-ray crystal diffraction data Diffraction angle: 2θ(°)(angstrom) spacing: d value 8.66 10.2 13.6 6.50 17.5 5.07 21.4 4.15

Example 1612-[[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride

(1) To a suspension of 4-benzyloxyphthalic anhydride (2.54 g, 10 mmol)in ethanol (30 mL) was added 20% sodium ethoxide ethanol solution (3.74g, 11 mmol) and the mixture was stirred at room temperature for 1 h. Thereaction mixture was poured into 1N hydrochloric acid (150 mL) andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (200 mL)and tert-butyl 2-(isobutylamino)acetate (2.25 g, 12 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g, 12mmol) and 1-hydroxybenzotriazole (1.84 g, 12 mmol) were added and themixture was stirred at room temperature for 3 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved inethanol (30 mL) and a solution (6.80 g, 20 mmol) of 20% sodium ethoxidein ethanol was added thereto. The mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into 1Nhydrochloric acid (20 mL) and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography and the component eluted earlier wasconcentrated to give tert-butyl7-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(0.40 g, 9.5%) as an oil.

¹H-NMR(CDCl₃) δ: 0.82 (6H, d, J=6.6 Hz), 1.78–1.87 (1H, m), 3.99 (3H,s), 4.39 (2H, d, J=7.5 Hz), 5.25 (2H, s), 7.25–7.48 (6H, m), 7.96–7.98(1H, m), 8.10 (1H, d, J=8.7 Hz), 11.34 (1H, s).

The component eluted later was concentrated to give tert-butyl6-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(1.51 g, 35.7%) as crystals.

Melting point 133–134° C. Elemental analysis for C₂₅H₂₉NO₅ Calculated:C, 70.90; H, 6.90; N, 3.31. Found: C, 70.84; H, 6.85; N, 3.11.¹H-NMR(CDCl₃) δ: 0.81 (6H, d, J=6.6 Hz), 1.64 (9H, s), 1.73–1.84 (1H, m)4.38 (2H, d, J=7.4 Hz), 5.21 (2H, s), 7.29 (1H, dd, J=2.4, 8.8 Hz),7.35–7.51 (5H, m), 7.58 (1H, d, J=2.4 Hz), 8.37 (1H, d, J=8.8 Hz), 11.17(1H, s).

(2) To a solution of tert-butyl6-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(6.35 g, 15 mmol) in N,N-dimethylformamide (50 mL) was added sodiumhydride (0.72 g, 18 mmol) (60% in oil) at 0° C. and the mixture wasstirred at 0° C. for 30 min. To the obtained mixture was addedN-phenyltrifluoromethanesulfonimide (6.43 g, 18 mmol) and the mixturewas stirred at room temperature for 2 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. After washing the extractwith water, the extract was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give tert-butyl6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(6.62 g, 81.2%) as an oil.

¹H-NMR(CDCl₃) δ: 0.89 (6H, d, J=6.6 Hz), 1.64 (9H, s), 2.04–2.15 (1H,m), 4.03 (2H, d, J>7.4 Hz), 5.18 (2H, s), 7.20–7.56 (7H, m), 8.34 (1H,d, J=9.2 Hz).

(3) A mixed solution of tert-butyl6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(6.52 g, 12 mmol), phenylboronic acid (1.76 g, 14.4 mmol) and sodiumcarbonate (3.18 g, 30 mmol) in toluene (50 mL), ethanol (10 mL) andwater (10 mL) was stirred under an argon atmosphere at room temperaturefor 10 min. To the obtained mixture was addedtetrakis(triphenylphosphine)-palladium (0.69 g, 0.6 mmol) and themixture was refluxed under heating under an argon atmosphere for 10 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give tert-butyl6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate(5.01 g, 86.4%) as crystals.

Melting point 138–139° C. Elemental analysis for C₃₁H₃₃NO₄ Calculated:C, 76.99; H, 6.88; N, 2.90 Found: C, 77.04; H, 6.80; N, 2.70.¹H-NMR(CDCl₃) δ: 0.94 (6H, d, J=6.9 Hz), 1.15 (9H, s), 2.17–2.27 (1H,m), 3.98 (2H, d, J=7.5 Hz), 4.95 (2H, s), 6.53 (1H, d, J=2.4 Hz), 7.13(1H, dd, J=2.4, 8.8 Hz), 7.25–7.36 (6H, m), 7.40–7.45 (4H, m), 8.41 (1H,d, J=8.8 Hz).

(4) A solution of tert-butyl6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate(9.03 g, 25 mmol) in trifluoroacetic acid (30 mL) was stirred at roomtemperature for 3 h. The reaction mixture was concentrated under reducedpressure and the obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylicacid (3.50 g, 82.0%) as crystals.

¹H-NMR(CDCl₃) δ: 0.85 (6H, d, J=6.6 Hz), 2.09–2.14 (1H, m), 3.83 (2H, d,J=7.5 Hz), 4.96 (2H, s), 6.58 (1H, d, J=2.4 Hz), 7.09–7.44 (11H, m),8.29 (1H, d, J=8.7 Hz).

(5) To a solution of6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylicacid (3.42 g, 8 mmol) in tetrahydrofuran (30 mL) were added oxalylchloride (0.84 mL, 9.6 mmol) and N,N-dimethylformamide (3 drops), andthe mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL). The obtained solution was addeddropwise to a suspension of sodium tetrahydroborate (1.06 g, 28 mmol) in1,2-dimethoxyethane (20 mL) at 0° C. The obtained mixture was stirred at0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(2.92 g, 88.5%) as crystals.

¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 2.16–2.40 (2H, m), 4.18 (2H, d,J=7.5 Hz), 4.43 (2H, s), 4.89 (2H, s), 6.37 (1H, d, J=2.4 Hz), 7.00 (1H,dd, J=2.4, 9.0 Hz), 7.21–7.34 (7H, m), 7.44–7.52 (3H, m), 8.30 (1H, d,J=9.0 Hz).

(6) To a suspension of6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(2.89 g, 7 mmol) in toluene (30 mL) was added thionyl chloride (1.0 mL,14 mmol). The obtained mixture was refluxed under heating for 2 h. Thereaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-benzyloxy-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(2.61 g, 86.4%) as crystals.

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 2.12–2.31 (1H, m), 4.16 (2H, d,J=7.4 Hz), 4.37 (2H, s), 4.93 (2H, s), 6.41 (1H, d, J=2.3 Hz), 7.13 (1H,dd, J=2.3, 9.0 Hz), 7.19–7.35 (7H, m), 7.45–7.54 (3H, m), 8.41 (1H, d,J=9.0 Hz).

(7) A solution of6-benzyloxy-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(2.59 g, 6 mmol) and potassium phthalimide (1.67 g, 9 mmol) inN,N-dimethylformamide (30 mL) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give2-[(6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(3.04 g, 93.5%) as crystals.

Melting point 113–114° C. Elemental analysis for C₃₅H₃₀N₂O₄ 0.25H₂OCalculated: C, 76.83; H, 5.62; N, 5.12. Found: C, 76.68; H, 5.79; N,4.93. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.4 Hz), 2.14–2.28 (1H, m), 4.04(2H, d, J=8.4 Hz), 4.76 (2H, s), 4.91 (2H, s), 6.36 (1H, d, J=2.6 Hz),7.10 (1H, dd, J=2.6, 8.8 Hz), 7.20–7.39 (10H, m), 7.66–7.76 (4H, m),8.39 (1H, d, J=8.8 Hz).

(8) To a solution of2-[(6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione(2.98 g, 5.5 mmol) in ethanol (30 mL) was added hydrazine monohydrate(0.8 mL, 16.5 mmol). The obtained mixture was refluxed under heating for1 h. The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (20 mL) and di-t-butyl dicarbonate, (1.9 mL, 8.3 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-diisopropyl ether togivetert-butyl(6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(2.29 g, 81.2%) as crystals.

Melting point 141–142° C. Elemental analysis for C₃₂H₃₅N₂O₄ Calculated:C, 74.97; H, 7.08; N, 5.46. Found: C, 74.60; H, 7.13; N, 5.45.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 1.42 (9H, s), 2.16–2.30 (1H,m), 4.03 (2H, d, J=7.4 Hz), 4.17 (2H, d, J=5.6 Hz), 4.45 (1H, bs), 4.92(2H, s), 6.35 (1H, d, J=2.4 Hz), 7.09 (1H, dd, J=2.4, 9.0 Hz), 7.17–7.37(7H, m), 7.47–7.52 (3H, m), 8.38 (1H, d, J=9.0 Hz).

(9) A suspension oftert-butyl(6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(2.05 g, 4 mmol) and 5% palladium carbon (0.6 g) in tetrahydrofuran (10mL) and ethanol (10 mL) was stirred under a hydrogen atmosphere at roomtemperature for 2 h. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The obtained crystals wererecrystallized from ethyl acetate-diisopropyl ether to givetert-butyl(6-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(1.56 g, 92.3%) as crystals.

Melting point 218–219° C. Elemental analysis for C₂₅H₃₀N₂O₄ Calculated:C, 71.07; H, 7.16; N, 6.63. Found: C, 70.85; H, 7.10; N, 6.62.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.8 Hz), 1.42 (9H, s), 2.14–2.24 (1H,m), 4.02 (2H, d, J=7.2 Hz), 4.18 (2H, d, J=5.4 Hz), 4.47 (1H, bs), 6.33(1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.20–7.27 (2H, m),7.43–7.46 (3H, m), 7.97 (1H, bs), 8.30 (1H, d, J=8.8 Hz).

(10) A solution oftert-butyl(6-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.63 q, 1.5 mmol), 2-iodoacetamide (0.43 g, 2.3 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.34 mL, 2.3 mmol) inN,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give tert-butyl6-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.32 g, 44.4%) as crystals.

Melting point 226–227° C. Elemental analysis for C₂₇H₃₃N₃O₅ Calculated:C, 67.62; H, 6.94; N, 8.76 Found: C, 67.36; H, 6.73; N, 8.60.¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.38 (9H, s), 2.07–2.21 (1H,m), 3.88 (2H, d, J=6.6 Hz), 3.95 (2H, d, J=4.0 Hz), 4.34 (2H, s), 6.30(1H, d, J=2.4 Hz), 7.13 (1H, dd, J=2.4, 8.8 Hz), 7.34–7.52 (8H, m), 8.24(1H, d, J=8.8 Hz).

(11) To a solution oftert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.24 g, 0.5 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diethyl ether to give2-[[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride (0.19 g, 95.0%) as crystals.

Melting point 185–186° C. Elemental analysis for C₂₂H₂₆N₃O₃Cl 0.5H₂OCalculated: C, 62.23; H, 6.44; N, 9.75. Found: C, 62.18; H, 6.40; N,9.89. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 2.01–2.18 (1H, m), 3.37(2H, bs), 3.85 (2H, bs), 4.05 (2H, d, J=6.8 Hz), 4.36 (2H, s), 6.30 (1H,d, J=2.0 Hz), 7.19 (1H, dd, J=2.0, 8.8 Hz), 7.36–7.40 (2H, m),7.52–7.58(3H, m), 8.28 (1H, d, J=8.8 Hz), 8.55 (3H, s).

Example 1622-[[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy]acetamide

(1) To a solution oftert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.38 g, 0.8 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 2 h. The reaction, mixture wasconcentrated under reduced pressure, and the residue was suspended in 1Naqueous sodium hydroxide solution. The suspension was stirred at roomtemperature for 10 min, and the reaction mixture was poured into waterand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The precipitated crystals were recrystallized from ethylacetate-diisopropyl ether to give2-[[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy]acetamide(0.19 g, 63.3%) as crystals.

Melting point 161–163° C. Elemental analysis for C₂₂H₂₅N₃O₃ 0.25H₂OCalculated: C, 68.82; H, 6.69; N, 10.94. Found: C, 69.02; H, 6.71; N,10.80. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 1.29 (2H, bs), 2.18–3.66(2H, s), 4.19 (2H, d, J=7.4 Hz), 4.32 (2H, s), 5.81 (1H, bs), 6.30 (1H,d, J=2.4 Hz), 6.51 (1H, bs), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.24–7.29(2H, m), 7.44–7.56 (3H, m), 8.43 (1H, d, J=8.8 Hz), 8.55 (3H, s).

Example 163(E)-3-[3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride

(1) To a solution of4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (4.60 g, 10 mmol) and N-methylmorpholine (1.3 mL, 12 mmol) intetrahydrofuran (30 mL) was added ethyl chloroformate (1.2 mL, 12 mmol)at 0° C. and the mixture was stirred at 0° C. for 10 min. To theobtained mixture were added sodium tetrahydroborate (1.13 g, 30 mmol)and methanol (5 mL), and the mixture was stirred at 0° C. for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The precipitatedcrystals were recrystallized from ethyl acetate-diisopropyl ether togivetert-butyl(4-butoxy-6-hydroxymethyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(2.89 g, 64.8%) as crystals.

Melting point 92–93° C. Elemental analysis for C₂₅H₃₈N₂O₅ Calculated: C,67.24; H, 8.58; N, 6.27. Found: C, 67.09; H, 8.43; N, 6.25.¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.01 (3H, t, J=7.4 Hz), 1.46–1.63 (11H,m), 1.77–1.92 (2H, m), 2.80 (1H, bs), 3.85 (2H, t, J=6.8 Hz), 4.14 (2H,bs), 4.56 (2H, d, J=5.0 Hz), 4.82 (2H, s), 5.15 (1H, bs), 7.42 (1H, d,J=8.4 Hz), 7.53 (1H, s), 8.19 (1H, d, J=8.4 Hz).

(2) To a solution oftert-butyl(4-butoxy-2-cyclopropylmethyl-6-formyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(2.27 g, 6.2 mmol) in tetrahydrofuran (30 mL) was added manganesedioxide (8.1 g) and the mixture was stirred at room temperature for 12h. Manganese dioxide was filtered off and the mother liquor wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to givetert-butyl(4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(2.52 g, 91.6%) as crystals.

Melting point 149–150° C. Elemental analysis for C₂₅H₃₈N₂O₅ 0.25H₂OCalculated: C, 66.87; H, 8.19; N, 6.24. Found: C, 67.09; H, 8.15; N,6.05. ¹H-NMR(CDCl₃) δ: 1.01 (9H, s), 1.06 (3H, t, J=7.4 Hz), 1.45 (9H,s), 1.52–1.71 (2H, m), 1.84–1.98 (2H, m), 3.91 (2H, t, J=6.4 Hz), 4.18(2H, bs), 4.61 (2H, d, J=5.4 Hz), 4.72 (1H, bs), 7.96 (1H, dd, J=1.7,8.4 Hz), 7.53 (1H, d, J=1.7 Hz), 8.55 (1H, d, J=8.4 Hz), 10.19 (1H, s).

(3) To a solution of ethyl diethylphosphonoacetate (1.1 mL, 5.5 mmol) inN,N-dimethylformamide (30 mL) was added sodium hydride (0.22 g, 5.5mmol) (60% in oil), and the mixture was stirred at room temperature for10 min. To the obtained mixture was added a solution of tert-butyl(4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(2.45 g, 5.5 mmol) in N,N-dimethylformamide (10 mL) and the mixture wasstirred at room temperature for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give ethyl(E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate(2.03 g, 71.7%), as an amorphous.

¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.06 (3H, t, J=7.4 Hz), 1.37 (3H, t,J=7.2 Hz), 1.45 (9H, s), 1.51–1.66 (2H, m), 1.82–1.93 (2H, m), 3.88 (2H,t, J=6.6 Hz), 4.14 (2H, bs), 4.30 (2H, q, J=7.2 Hz), 4.58 (2H, d, J=5.2Hz), 4.71 (1H, bs), 6.58 (1H, d, J=16.2 Hz), 7.65 (1H, dd, J=1.6, 8.4Hz), 7.77 (1H, d, J=1.6 Hz), 7.79 (1H, d, J=16.2 Hz), 8.39 (1H, d, J=8.4Hz).

(4) To a solution of ethyl(E)-3-[4-butoxy-3[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate(0.67 g, 1.3 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) as added1N sodium hydroxide (3 mL). The obtained mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl-acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-n-hexane to give(E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.53 g, 84.1%) as crystals.

Melting point 138–139° C. Elemental analysis for C₂₇H₃₈N₂O₆ Calculated:C, 66.64; H, 7.87; N, 5.76. Found: C, 66.57; H, 7.84; N, 5.57.¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.07 (3H, t, J=7.3 Hz), 1.48 (9H, s),1.49–1.67 (2H, m), 1.83–1.94 (2H, m), 3.88 (2H, t, J=6.6 Hz), 4.14 (2H,bs), 4.59 (2H, d, J=4.8 Hz), 5.32 (1H, bs), 6.57 (1H, d, J=15.7 Hz),7.58 (1H, d, J=8.5 Hz), 7.68 (1H, s), 7.83 (1H, d, J=15.7 Hz), 8.29 (1H,d, J=8.5 Hz).

(5) A solution of(E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.34 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammoniumsalt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 mL) was stirred atroom temperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give(E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.29 g, 87.9%) as crystals.

Melting point 121–122° C. Elemental analysis for C₂₇H₃₉N₃O₅ 0.5H₂OCalculated: C, 65.56; H, 8.15; N, 8.50. Found: C, 66.18; H, 8.06; N,8.59. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.05 (3H, t, J=7.2 Hz), 1.46 (9H,s), 1.53–1.65 (2H, m), 1.83–1.93 (2H, m), 3.88 (2H, t, J=6.5 Hz), 4.18(2H, bs), 4.58 (2H, d, J=4.8 Hz), 4.92 (1H, bs), 5.74 (1H, bs), 5.91(1H, bs), 6.60 (1H, d, J=15.6 Hz), 7.58 (1H, dd, J=1.5, 8.4 Hz), 7.73(1H, d, J=1.5 Hz), 7.75 (1H, d, J=15.6 Hz), 8.31 (1H, d, J=8.4 Hz).

(6) To a solution of(E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.24 g, 0.5 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diethyl ether to give(E)-3-[3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride (0.19 g, 90.5%) as crystals.

Melting point 187–188° C. Elemental analysis C₂₂H₃₂N₃O₃Cl 0.75H₂OCalculated: C, 60.68; H, 7.75; N, 9.65. Found: C, 60.53; H, 7.74; N,9.73. ¹H-NMR(DMSO-d₆) δ: 0.91 (9H, s), 1.01 (3H, t, J=7.3 Hz), 1.52–1.63(2H, m), 1.82–1.93 (2H, m), 3.96 (2H, t, J=6.3 Hz), 4.12 (2H, bs), 4.24(2H, bs), 4.91 (1H, bs), 6.84 (1H, d, J=15.8 Hz), 7.29 (1H, bs), 7.63(1H, d, J=15.8 Hz), 7.81 (1H, d, J=8.4 Hz), 7.87 (1H, bs), 8.29 (1H, d,J=8.4 Hz), 8.58 (3H, bs).

Example 1642-[[3-(Aminomethyl)-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride

(1) A solution of 4-benzyloxyphthalic anhydride (4.07 g, 16 mmol) andethyl 2-(isobutylamino)acetate (2.86 g, 18 mmol) in tetrahydrofuran (30mL) was stirred at room temperature for 1 h. The reaction mixture waspoured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (30 mL), and potassium carbonate (2.21 g, 16 mmol)and ethyl iodide (1.5 mL, 19.2 mmol) were added thereto. The mixture wasstirred at room temperature for 3 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in ethanol (50 mL), and asolution (10.9 g, 32 mmol) of 20% sodium ethoxide in ethanol was addedthereto. The mixture was stirred at room temperature for 1 h. Thereaction mixture was poured into 1N hydrochloric acid (70 mL) andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyand the component eluted earlier was concentrated to give ethyl7-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(4.21 g, 66.6%) as an oil.

¹H-NMR(CDCl₃) δ: 0.82 (6H, d, J=6.6 Hz), 1.45 (3H, t, J=7.1 Hz),1.77–1.91 (1H, m), 4.42–4.52 (4H, m), 7.31–7.58(6H, s), 7.97 (1H, d,J=2.6 Hz), 8.10 (1H, d, J=8.8 Hz), 11.45 (1H, s).

The component eluted later was concentrated to give ethyl6-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(0.80 g, 12.7%) as crystals.

Melting point 92–93° C. Elemental analysis for C₂₃H₂₅NO₅ Calculated: C,69.86; H, 6.37; N, 3.54. Found: C, 69.68; H, 6.20; N, 3.51.¹H-NMR(CDCl₃) δ: 0.81 (6H, d, J=6.6 Hz), 1.46 (3H, t, J=7.22 Hz),1.73–1.87 (1H, m), 4.39 (2H, d, J=7.2 Hz), 4.48 (2H, q, J=7.2 Hz), 5.21(2H, s), 7.28–7.49 (6H, m), 7.60 (1H, d, J=2.6 Hz), 8.38 (1H, d, J=8.8Hz), 11.23 (1H, s).

(2) To a solution of ethyl6-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(5.93 g, 15 mmol), 4,4,4-trifluorobutanol (2.31 g, 18 mmol) andtributylphosphine (7.5 ml, 30 mmol) in tetrahydrofuran (50 mL) was added1,1′-(azodicarbonyl)dipiperidine (7.57 g, 30 mmol) and the mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography to give ethyl6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylate(6.71 g, 88.5%) as an oil.

¹H-NMR(CDCl₃) δ: 0.89 (6H, d, J=6.6 Hz), 1.43 (3H, t, J=7.2 Hz),1.90–2.37 (5H, m), 3.83–3.92 (4H, m), 4.43 (2H, q, J=7.2 Hz), 5.22 (2H,s), 7.03 (1H, d, J=2.4 Hz), 7.21 (1H, dd, J=2.4, 9.0 Hz), 7.33–7.46 (5H,m), 8.37 (1H, d, J=9.0 Hz).

(3) To a solution of ethyl6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylate(6.57 g, 13 mmol) in ethanol (50 mL) was added an aqueous solution (20mL) of sodium hydroxide (2.08 g, 52 mmol). The obtained mixture wasrefluxed under heating for 12 h. The reaction mixture was poured intowater acidified with 1N hydrochloric acid and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium, sulfate and concentrated under reduced pressure. Theobtained, crystals were recrystallized from ethyl acetate-n-hexane togive6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylicacid (4.89 g, 78.7%) as crystals.

Melting point 130–131° C. ¹H-NMR(CDCl₃) δ: 0.85 (6H, d, J=6.4 Hz),1.92–2.39 (5H, m), 3.89–3.93 (4H, m), 5.16 (2H, s), 6.79 (1H, d, J=2.6Hz), 7.71 (1H, dd, J=2.6, 8.8 Hz), 7.32–7.41 (5H, m), 8.18 (1H, d, J=8.8Hz).

(4)6-Benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinecarboxylicacid (4.77 g, 10 mmol) was dissolved in tetrahydrofuran (50 mL), andoxalyl chloride (1.1 mL, 12 mmol) and N,N-dimethylformamide (3 drops)were added. The mixture was stirred at room temperature for 1 h. Thereaction mixture was concentrated under reduced pressure and the residuewas dissolved in tetrahydrofuran (20 mL). The obtained solution wasadded dropwise to a suspension of sodium tetrahydroborate (1.32 g, 35mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. The obtained mixture wasstirred at 0° C. for 1 h. The reaction mixture was poured into 1Nhydrochloric acid and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained crystals wererecrystallized from ethyl acetate-n-hexane to give6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone-(4.02g, 84.6%) as crystals.

Melting point 112–113° C. Elemental analysis for C₂₅H₂₈NO₄F₃ Calculated:C, 65.67; H, 5.94; N, 2.95. Found: C, 65.77; H, 6.21; N, 3.03.¹H-NMR(CDCl₃) δ: 0.91 (6H, d, J=6.6 Hz), 1.97–2.43 (5H, m), 2.56 (1H,bs), 3.83 (2H, t, J=6.2 Hz), 4.03 (2H, d, J=7.4 Hz), 4.76 (2H, d, J=5.6Hz), 5.20 (2H, s), 6.94 (1H, d, J=2.2 Hz), 7.12 (1H, dd, J=2.2, 8.8 Hz),7.30–7.45 (5H, m), 8.27 (1H, d, J=8.8 Hz).

(5) To a solution of6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone(3.80 g, 8 mmol) in toluene (30 mL) was added thionyl chloride (1.2 mL,16 mmol). The obtained mixture was refluxed under heating for 2 h. Thereaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone(3.4 g, 88.8%) as an oil.

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 2.00–2.46 (5H, m), 3.91 (2H, t,J=6.2 Hz), 4.04 (2H, d, J=7.6 Hz), 4.76 (2H, s), 5.23 (2H, s), 7.02 (1H,d, J=2.6 Hz), 7.12–7.46 (6H, m), 8.38 (1H, d, J=8.8 Hz).

(6) A solution of6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone(3.37 g, 7 mmol) and potassium phthalimide (1.94 g, 10.5 mmol) inN,N-dimethylformamide (30 mL) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, and the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-n-hexane to give2-[[6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(3.91 g, 94.4%) as crystals.

Melting point 131–132° C. Elemental analysis for C₃₃H₃₁N₂O₅F₃Calculated: C, 66.88; H, 5.27; N, 4.73. Found: C, 67.25; H, 5.21; N,4.84. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.95–2.40 (5H, m), 3.93(2H, t, J=6.4 Hz), 4.05 (2H, d, J=7.8 Hz), 4.97 (2H, s), 5.21 (2H, s),6.98 (1H, d, J=2.6 Hz), 7.16 (1H, dd, J=2.6, 8.8 Hz), 7.28–7.45 (5H, m),7.68–7.87 (4H, m), 8.35 (1H, d, J=8.8 Hz).

(7) To a solution of2-[[6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(3.85 g, 6.5 mmol) in ethanol (30 mL) was added hydrazine monohydrate(0.95 mL, 19.5 mmol). The obtained mixture was refluxed under heatingfor 2 h. The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL) and di-t-butyl dicarbonate (2.2 mL, 9.8 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-diisopropyl ether togivetert-butyl[6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]-methylcarbamate(0.36 g, 87.8%) as crystals.

Melting point 117–118° C. Elemental analysis for C₃₂H₃₇N₂O₅F₃Calculated: C, 64.04; H, 6.63; N, 4.98. Found: C, 64.33; H, 6.75; N,5.00. ¹H-NMR(CDCl₃) δ: 0.94 (6H, d, J=7.0 Hz), 1.46 (9H, s), 1.98–2.44(5H, m), 3.78 (2H, t, J=6.2 Hz), 3.93 (2H, d, J=7.8 Hz), 4.46 (2H, d,J=5.2 Hz), 4.72 (1H, bs), 5.22 (2H, s), 6.97 (1H, d, J=2.4 Hz), 7.16(1H, dd, J=2.4, 9.0 Hz), 7.31–7.46 (5H, m), 8.34 (1H, d, J=9.0 Hz).

(8) A suspension oftert-butyl[6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(3.09 g, 5.5 mmol) and 5% palladium carbon (1.0 g) in tetrahydrofuran(20 mL) and ethanol (20 mL) was stirred under a hydrogen atmosphere atroom temperature for 2 h. The catalyst was filtered off and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography to givetert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.48 g, 95.4%) as crystals.

Melting point 173–174° C. Elemental analysis for C₂₃H₃₁N₂O₅F₃Calculated: C, 58.47; H, 6.61; N, 5.93. Found: C, 58.61; H, 6.66; N,5.84. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=7.0 Hz), 1.47 (9H, s), 2.03–2.45(5H, m), 3.88 (2H, t, J=5.9 Hz), 3.98 (2H, d, J=7.4 Hz), 4.49 (2H, d,J=4.6 Hz), 4.77 (1H, bs), 7.08–7.14 (2H, m), 8.26 (1H, d, J=8.8 Hz),8.86 (1H, bs).

(9) A solution oftert-butyl[6-hydroxy-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1–1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.47 g, 1 mmol), iodoacetamide (0.27 g, 1.5 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.22 mL, 1.5 mmol) inN,N-dimethylformamide (10 mL) was stirred at 70° C. for 12 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.25 g, 48.1%) as crystals.

Melting point 184–186° C. Elemental analysis for C₂₅H₃₄N₃O₆F₃Calculated: C, 56.70; H, 6.47; N, 7.94. Found: C, 56.43; H, 6.55; N,7.87. ¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.47 (9H, s), 2.05–2.23(2H, m), 2.32–2.52 (2H, m), 3.91 (2H, t, J=6.4 Hz), 3.96 (2H, d, J=7.6Hz), 4.49 (2H, d, J=5.9 Hz), 4.62 (2H, s), 4.74 (1H, bs), 5.81 (1H, bs),6.54 (1H, bs), 7.00 (1H, d, J=2.6 Hz), 7.10 (1H, dd, J=2.6, 8.8 Hz),8.38 (1H, d, J=8.8 Hz).

(10) To a solution oftert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.18 g, 0.35 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen, chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the precipitated crystals wererecrystallized from methanol-diisopropyl ether to give2-[[3-(aminomethyl)-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride (0.15 g, 93.8%) as crystals.

Melting point 147–148° C. Elemental analysis for C₂₀H₂₇N₃O₄ClF₃ H₂OCalculated: C, 49.64; H, 6.04; N, 8.68. Found: C, 49.73; H, 5.97; N,8.60. ¹H-NMR(DMSO-d₆) δ: 0.88 (6H, d, J=6.6 Hz), 1.96–2.13 (3H, m),2.56–2.71 (2H, m), 3.93–4.02 (4H, m), 4.15 (2H, d, J=4.2 Hz), 4.67 (2H,s), 7.05 (1H, d, J=2.4 Hz), 7.24 (1H, dd, J=2.4, 8.8 Hz), 7.49 (1H, bs),7.76 (1H, bs), 8.20 (1H, d, J=8.8 Hz), 8.73 (3H, s).

Example 1652-[[3-(Aminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride

(1) A mixed solution of methyl6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(7.70 g, 15 mmol), 4-fluorophenylboronic acid (2.52 g, 18 mmol) andsodium carbonate (3.97 g, 37.5 mmol) in toluene (50 mL), methanol (10mL) and water (10 mL) was stirred under an argon atmosphere at roomtemperature for 30 min. To the obtained mixture was addedtetrakis(triphenylphosphine)palladium (0.87 g, 0.9 mmol) and the mixturewas refluxed under heating under an argon atmosphere for 12 h. Thereaction mixture was poured into water and extracted with ethyl acetate.After washing the extract with water, the extract was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give methyl6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(5.16 g, 74.9%) as crystals.

Melting point 118–119° C. Elemental analysis for C₂₈H₂₆NO₄F Calculated:C, 73.19; H, 5.70; N, 3.05. Found: C, 72.92; H, 5.79; N, 2.97.¹H-NMR(CDCl₃) δ: 0.92 (6H, d, J=6.6 Hz), 2.02–2.21 (1H, m), 3.49 (3H,s), 3.93 (2H, d, J=7.8 Hz), 4.99 (2H, s), 6.54 (1H, d, J=2.4 Hz),7.07–7.40 (10H, m), 8.43 (1H, d, J=8.8 Hz).

(2) To a solution of methyl6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(5.05 g, 11 mmol) in methanol (30 mL) was added an aqueous solution (10mL) of lithium hydroxide monohydrate (1.38 g, 33 mmol). The obtainedmixture was refluxed under heating for 12 h. The reaction mixture waspoured into water, and, acidified with 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (3.94 g, 80.5%) as crystals.

Melting point 236–237° C. Elemental analysis for C₂₇H₂₄NO₄F Calculated:C, 72.80; H, 5.43; N, 3.14. Found: C, 72.41; H, 5.28; N, 3.02.¹H-NMR(CDCl₃) δ: 0.86 (6H, d, J=6.6 Hz), 2.10–2.24 (1H, m), 3.89 (2H, d,J=7.4 Hz), 4.99 (2H, s), 6.52 (1H, d, J=2.2 Hz), 7.04–7.16 (3H, m),7.24–7.37 (7H, m), 8.25 (1H, d, J=9.2 Hz).

(3) To a solution of6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (3.79 g, 8.5 mmol) in tetrahydrofuran (30 mL) were added oxalylchloride (0.9 mL, 10.2 mmol) and N,N-dimethylformamide (3 drops), andthe mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL). The obtained solution was addeddropwise to a suspension of sodium tetrahydroborate (1.13 g, 30 mmol) in1,2-dimethoxyethane (30 mL) at 0° C. The obtained mixture was stirred at0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give6-benzyloxy-4-(4-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(3.31 g, 90.2%) as crystals.

Melting point 143–144° C. Elemental analysis for C₂₇H₂₆NO₃F Calculated:C, 75.15; H, 6.07; N, 3.25. Found C, 75.04; H, 6.28; N, 3.22.¹H-NMR(CDCl₃) δ: 0.94 (6H, d, J=6.6 Hz), 2.11–2.25 (1H, m), 2.70 (1H,bs), 4.16 (2H, d, J=7.8 Hz), 4.41 (2H, d, J=5.4 Hz), 4.89 (2H, s), 6.28(1H, d, J=2.4 Hz), 6.93–6.98 (1H, m), 7.13–7.34 (9H, m), 8.20–8.26 (1H,m).

(4) To a suspension of6-benzyloxy-4-(4-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(3.24 g, 7.5 mmol) in toluene (50 mL) was added thionyl chloride (1.1mL, 15 mmol). The obtained mixture was refluxed under heating for 2 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-benzyloxy-3-chloromethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(3.18 g, 94.4%) as crystals.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 2.13–2.31 (1H, m), 4.14 (2H, d,J=7.6 Hz), 4.35 (2H, s), 4.95 (2H, s), 6.35 (1H, d, J=2.6 Hz), 7.11–7.38(10H, m), 8.41 (1H, d, J=8.8 Hz).

(5) A solution of6-benzyloxy-3-chloromethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone(3.15 g, 7 mmol) and potassium phthalimide (1.94 g, 10.5 mmol) inN,N-dimethylformamide (100 mL) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-diisopropylether to give2-[[6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(3.42 g, 87.2%) as crystals.

Melting point 198–199° C. Elemental analysis for C₃₅H₂₉N₂O₄F Calculated:C, 74.98; H, 5.21; N, 5.00. Found: C, 74.83; H, 5.01; N, 4.82.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.13–2.27 (1H, m), 4.02 (2H, d,J=7.4 Hz), 4.94 (2H, s), 6.31 (1H, d, J=2.6 Hz), 7.02–7.14 (3H, m),7.20–7.38 (7H, m), 7.66–7.78 (4H, m), 8.39 (1H, d, J=9.2 Hz).

(6) To a solution of2-[[6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(3.36 g, 6 mmol) in ethanol (30 mL) was added hydrazine monohydrate (0.9mL, 18 mmol). The obtained mixture was refluxed under heating for 2 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (20 mL) and di-t-butyl dicarbonate (2.1 mL, 9 mmol) wasadded thereto. The obtained mixture was stirred at room temperature for1 h. The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-diisopropyl ether togivetert-butyl[6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(3.16 g, 99.4%) as crystals.

Melting point 184–185° C. Elemental analysis for C₃₂H₃₅N₂O₄F Calculated:C, 72.43; H, 6.65; N, 5.28. Found: C, 72.07; H, 6.52; N, 5.18.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.14–2.27 (1H,m), 4.02 (2H, d, J=6.9 Hz), 4.15 (2H, d, J=5.4 Hz), 4.52 (1H, bs), 4.94(2H, s), 6.29 (1H, d, J=2.4 Hz), 7.06–7.11 (1H, m), 7.16–7.36 (9H, m),8.34–8.38 (1H, m).

(7) A suspension oftert-butyl[6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.65 g, 5 mmol) and 5% palladium carbon (0.8 g) in ethanol (20 mL) andtetrahydrofuran (20 mL) was stirred under a hydrogen atmosphere at roomtemperature for 2 h. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The obtained crystals wererecrystallized from tetrahydrofuran-diisopropyl ether to givetert-butyl[4-(4-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(3.11 g, 94.2%) as crystals.

Melting point 229–230° C. Elemental analysis for C₂₅H₂₉N₂O₄F Calculated:C, 68.16; H, 6.64; N, 6.36. Found: C, 67.98; H, 6.88; N, 6.20.¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.11–2.24 (1H, m)4.00 (1H, d, J=7.4 Hz), 4.16 (2H, d, J=3.6 Hz), 4.49 (1H, bs), 6.33 (1H,d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 9.0 Hz), 7.06–7.18 (4H, m), 7.90 (1H,bs), 8.26 (1H, d, J=9.0 Hz),

(8) A solution oftert-butyl[4-(4-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.44 g, 1 mmol), 2-iodoacetamide (0.37 g, 2 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.30 mL, 2 mmol) inN,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.24 g, 49.0%) as crystals.

Melting point 218–219° C. Elemental analysis for C₂₇H₃₂N₃O₅F Calculated:C, 65.18; H, 6.48; N, 8.45. Found: C, 64.84; H, 6.75; N, 8.25.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.13–2.30 (1H,m), 4.04 (2H, d, J=7.6 Hz), 4.17 (2H, d, J=5.6 Hz), 4.35 (2H, s), 4.54(1H, bs), 5.75 (1H, bs), 6.28 (1H, d, J=2.5 Hz), 6.49 (1H, bs), 7.04(1H, dd, J=2.5, 9.0 Hz), 7.21–7.24 (4H, m), 8.42 (1H, d, J=9.0 Hz).

(9) To a solution oftert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.20 g, 0.4 mmol) in ethyl acetate (5 mL) was added a solution of 4Nhydrogen chloride in ethyl acetate (5 mL) and the obtained solution wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the residue was crystallizedfrom ethyl acetate-diisopropyl, ether to give2-[[3-(aminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride (0.16 g, 94.1%) as crystals.

Melting point 189–190° C. Elemental analysis for C₂₂H₂₅N₃O₃FClCalculated: C, 65.18; H, 6.48; N, 8.45. Found: C, 64.84; H, 6.75; N,8.25. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.99–2.18 (1H, m), 3.84(2H, bs), 4.04 (2H, d, J=6.6 Hz), 4.38 (2H, s), 6.29 (1H, d, J=2.0 Hz),7.20 (1H, dd, J=2.0, 9.0 Hz), 7.34 (1H, bs), 7.38–7.43 (4H, m), 7.56(1H, bs), 8.27 (1H, d, J=9.0 Hz), 8.53 (3H, bs).

Example 1663-(Aminomethyl)-2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-3-yl)-4-phenyl-1(2H)-isoquinolinone

(1) A mixture of methyl3-{[((tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxylate(0.24 g, 0.53 mmol), hydrazine monohydrate (0.65 mL, 13.3 mmol) andmethanol (6 mL) was stirred in a sealed tube at 75° C. The reactionmixture was concentrated under reduced pressure and to the residue wasadded methanol-water (1:1, 4 mL) to allow precipitation of a solid. Thissolid was collected by filtration, washed with water and dried in vacuoto givetert-butyl[6-(hydrazinocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.23 g, 94%) as a colorless solid.

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.15–2.35 (1H,m), 4.08 (2H, d, J=7.0 Hz), 4.20 (2H, d, J=5.2 Hz), 4.70 (1H, br),7.20–7.30 (3H, m), 7.45–7.55 (3H, m), 7.69 (1H, d, J=5.4 Hz), 8.43 (1H,d, J=8.6 Hz).

(2) A mixture oftert-butyl[6-(hydrazinocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.23 g, 0.50 mmol), triethyl orthoacetate (2.0 mL, 10.9 mmol) andn-butanol (10 mL) was refluxed under heating for 20 min. To the reactionmixture was added 1,8-diazabicyclo[5.4.0]-7-undecene (0.075 mL, 0.50mmol) and the mixture was refluxed under heating for 1 h. To thisreaction mixture was added acetic acid (0.040 mL, 0.70 mmol) and themixture was concentrated under reduced pressure. The residue waspartitioned between water (10 mL) and ethyl acetate (30 mL), and theorganic layer was washed with water (20 mL), dried over anhydrousmagnesium sulfate (9 g) and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=2:1 (v/v)) to givetert-butyl[2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-3-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.22 g, 91%) as a colorless powder.

¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=7.2 Hz), 1.43 (9H, s), 2.15–2.35 (1H,m), 2.57 (3H, s), 4.10 (2H, d, J=7.2 Hz), 4.22 (2H, d, J=5.4 Hz), 4.57(1H, br), 7.20–7.35 (2H, m), 7.50–7.65 (4H, m), 8.05 (1H, dm, J=8.4 Hz),8.58 (1H, dd, J=2.8, 8.4 Hz).

(3) Totert-butyl[2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-3-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.20 g, 0.41 mmol) was added a solution (4 mL) of 4N hydrogen chloridein ethyl acetate and the mixture was stirred at room temperature for 17h. The reaction mixture was concentrated under reduced pressure and tothe residue was added diisopropyl ether (5 mL). The precipitated powderwas collected by filtration. To this powder was added saturated aqueoussodium hydrogencarbonate (30 mL) and the mixture was extracted twicewith a solution (25 mL) of ethyl acetate-tetrahydrofuran (1:1). Theorganic layers were combined and the mixture was washed with saturatedbrine (25 mL), dried over anhydrous magnesium sulfate (15 g) andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate:methanol=20:1, (v/v)) andrecrystallized from n-hexane-ethyl acetate (5:1) to give the titlecompound (0.11 g, 72%) as pale-yellow crystals.

Elemental analysis for C₂₃H₂₄N₄O₂, Calculated: C, 71.11; H, 6.23; N,14.42. Found: C, 71.09; H, 6.28; N, 14.37. ¹H-NMR(CDCl₃) δ: 1.02 (6H, d,J=6.6 Hz), 2.15–2.40 (1H, m), 2.57 (3H, s), 3.69 (2H, bs), 4.24 (2H, d,J=7.4 Hz), 7.25–7.35 (2H, m), 7.45–7.60 (2H, m), 7.62 (1H, d, J=1.0 Hz),8.05 (1H, dd, J=1.6, 8.4 Hz), 8.59 (1H, d, J=8.4 Hz). Melting point179–181° C.

Example 1676-Acetyl-3-(aminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) To a mixture of3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxylicacid (0.81 g, 1.8 mmol), N,O-dimethylhydroxylamine hydrochloride (0.211g, 2.16 mmol), 1-hydroxy-1H-benzotriazole monohydrate (0.365 g, 2.7mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride(0.517 g, 2.7 mmol) and N,N-dimethylformamide (10 mL) was addedtriethylamine (0.301 mL, 2.16 mmol), and the mixture was stirred at roomtemperature for 17 h. The reaction mixture was poured into 0.1 M aqueouscitric acid solution (100 mL) and extracted 3 times with ethyl acetate(50 mL). The organic layers were combined, washed once with 0.1 Maqueous citric acid solution (50 mL), twice with saturated aqueoussodium hydrogencarbonate (50 mL) and once with saturated brine (50 mL),dried over anhydrous magnesium sulfate (15 g), and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:4 (v/v)) to givetert-butyl(2-isobutyl-6-{[methoxy(methyl)amino]carbonyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.83 g, 94%) as a colorless, solid.

¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.15–2.35 (1H,m), 3.27 (3H, s), 3.42 (3H, s), 4.09 (2H, d, J=7.2 Hz), 4.21 (2H, d,J=5.4 Hz), 4.43 (1H, br), 7.20–7.30 (3H, m), 7.45–7.55 (3H, m), 7.69(1H, dd, J=1.6, 8.2 Hz), 8.50 (1H, d, J=8.2 Hz).

(2)Tert-butyl(2-isobutyl-6-{[methoxy(methyl)amino]carbonyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.175 g, 0.355 mmol) was dissolved in tetrahydrofuran (5 mL) and asolution (0.15 mL, 0.43 mmol) of 3 M methyl magnesium bromide in diethylether was added dropwise under ice-cooling. This mixture was stirred atroom temperature for 1 h and quenched with saturated aqueous ammoniumchloride solution (5 mL). The whole was extracted with ethyl acetate (10mL), and the organic layer was washed once each with 0.1 M aqueouscitric acid solution (10 mL), saturated aqueous sodium hydrogencarbonate(10 mL) and saturated brine (10 mL), dried over anhydrous magnesiumsulfate (12 g) and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethyl acetate=5:2(v/v)) to givetert-butyl(6-acetyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.132 g, 83%) as a colorless powder.

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=7.2 Hz), 1.43 (9H, s), 2.15–2.35 (1H,m), 2.27 (3H, s), 4.10 (2H, d, J=7.2 Hz), 4.23 (2H, d, J=5.4 Hz), 4.49(1H, br), 7.20–7.30 (2H, m), 7.45–7.65 (4H, m), 7.96 (1H, dd, J=1.8, 8.4Hz), 8.54 (1H, d, J=8.4 Hz).

(3)Tert-butyl(6-acetyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.10 g, 0.22 mmol) was dissolved in ethyl acetate (4 mL) and a solution(1 mL) of 4N hydrogen chloride in ethyl acetate was added thereto. Themixture was stirred at room temperature for 17 h. The reaction mixturewas concentrated under reduced pressure and the residue was precipitatedfrom ethyl acetate-diisopropyl ether (1:10) to give the title compound(0.084 g, 98%) as a pale-yellow powder.

Elemental analysis for C₂₂H₂₄N₂O₂ HCl H₂O, Calculated:C, 65.58; H, 6.75;N, 6.95. Found: C, 66.25; H, 6.73; N, 6.83. ¹H-NMR(CD₃OD) δ: 1.02 (6H,d, J=6.6 Hz), 2.10–2.30 (1H, m), 2.50 (3H, s), 4.05–4.20 (4H, m),7.35–7.45 (2H, m), 7.55–7.70 (4H, m), 8.15 (1H, dd, J=1.4, 8.4 Hz), 8.53(1H, d, J=8.4 Hz). Melting point 179° C. (decomposition)

Example 1683-(Aminomethyl)-2-isobutyl-6-(1,3-oxazol-5-yl)-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) Tert-Butyl(6-formyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.20 g, 0.45 mmol) was dissolved in methanol (10 mL) and p-toluenesulfonylmethylisocyanide (0.088 g, 0.45 mmol) and potassium carbonate(0.125 g, 0.90 mmol) were added.

This mixture was refluxed under heating for 30 min and the reactionmixture was partitioned between saturated aqueous sodiumhydrogencarbonate (50 mL) and ethyl acetate-tetrahydrofuran (1:1 (v/v),50 mL). The organic layer was washed once each with saturated aqueoussodium hydrogencarbonate (50 mL) and saturated brine (50 mL), dried overanhydrous magnesium sulfate (12 g) and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1 (v/v)) to give tert-butyl[2-isobutyl-6-(1,3-oxazol-5-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.16 g, 75%) as a colorless solid.

¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.15–2.40 (1H,m), 4.09 (2H, d, J=7.2 Hz), 4.22 (2H, d, J=5.6 Hz), 4.51 (1H, br), 7.20(1H, d, J=1.4 Hz), 7.20–7.35 (2H, m), 7.31 (1H, s), 7.45–7.60 (3H, m),7.70 (1H, dd, J=1.4, 8.4 Hz), 7.86 (1H, s), 8.51 (1H, d, J=8.4 Hz).

(2)Tert-butyl[2-isobutyl-6-(1,3-oxazol-5-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.14 g, 0.30 mmol) was dissolved in methanol (4 mL) and a solution (10mL) of 4N hydrogen chloride in ethyl acetate were added thereto. Thismixture was stirred at room temperature for 1 h and the precipitatedcrystals were collected by filtration to give the title compound (0.084g, 69%) as a colorless powder.

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.10–2.20 (1H, m), 3.80–4.10(4H, m), 7.16 (1H, d, J=1.6 Hz), 7.40–7.50 (2H, m), 7.55–7.65 (3H, m),7.95–8.00 (1H, m), 8.30 (3H, br), 8.40 (1H, d, J=8.84 Hz), 8.43 (1H, s).Melting point 217° C. (decomposition)

Example 1693-(Aminomethyl)-2-isobutyl-4-phenyl-6-(2H-tetrazol-5-yl)-1(2H)-isoquinolinonehydrochloride

(1) To a solution (30 mL) oftert-butyl(6-cyano-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.86 g, 2.0 mmol) in toluene were added sodium azide (0.16 g, 2.5 mmol)and triethylamine hydrochloride (0.28 g, 2.5 mmol) and the mixture wasstirred at 90° C. for 24 h. The reaction mixture was poured into water(100 mL), acidified with 1N hydrochloric acid and extracted twice withethyl acetate (50 mL). The extracts were combined and washed withsaturated brine (15 mL), dried over anhydrous magnesium sulfate (12 g)and concentrated under reduced pressure. The residue was recrystallizedfrom tetrahydrofuran-diisopropyl ether (1:5) to give tert-butyl[2-isobutyl-1-oxo-4-phenyl-6-(2H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.36 g, 37%) as colorless crystals.

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.45 (9H, s), 2.15–2.35 (1H,m), 4.15 (2H, bd, J=7.4 Hz), 4.22 (2H, bd, J=5.0 Hz), 7.25–7.50 (6H, m),7.73 (1H, bs), 8.05 (1H, dm, J=8.4 Hz), 8.44 (1H, d, J=8.4 Hz).

(2)Tert-butyl[2-isobutyl-1-oxo-4-phenyl-6-(2H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.15 g, 0.32 mmol) was dissolved in tetrahydrofuran (4 mL) and asolution (4 mL) of 4N hydrogen chloride in ethyl acetate was addedthereto. This mixture was stirred at room temperature for 17 h, and theprecipitated crystals were collected by filtration to give the titlecompound (0.13 g, 97%) as colorless crystals.

Elemental analysis for C₂₁H₂₂N₆O HCl 0.5H₂O Calculated:C, 57.60; H,5.98; N, 19.19. Found: C, 57.41; H, 5.96; N, 18.73. ¹H-NMR(DMSO-d₆) δ:0.94 (6H, d, J=6.6 Hz), 2.10–2.20 (1H, m), 3.90 (2H, bs), 4.10 (2H, d,J=6.6 Hz), 7.40–7.50 (2H, m), 7.55–7.65 (3H, m), 7.69 (1H, d, J=1.5 Hz),8.23 (1H, dd, J=1.5, 8.1 Hz), 8.52 (3H, br), 8.54 (1H, d, J=8.1 Hz).Melting point 218–220° C.

Example 1703-(Aminomethyl)-2-isobutyl-6-(methylsulfanyl)-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) A mixture of3-(aminomethyl)-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (0.19g, 0.50 mmol), sodium thiomethoxide (0.043 g, 0.60 mmol) anddimethylsulfide (2 mL) was stirred at 70° C. for 2 h. To the reactionmixture was added another sodium thiomethoxide (0.043 g, 0.60 mmol), andthe resulting mixture was stirred at 70° C. for 2 h. The reactionmixture was partitioned between water (100 mL) and ethyl acetate (25 mL)and the aqueous layer was extracted with ethyl acetate (25 mL). Theextracts were combined and washed once each with saturated aqueoussodium hydrogencarbonate (25 mL) and saturated brine (25 mL), dried overanhydrous magnesium sulfate (12 g) and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:5 (v/v)) to give3-(aminomethyl)-2-isobutyl-6-(methylsulfanyl)-4-phenyl-1(2H)-isoquinolinone(0.16 g, 88%) as an oil.

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 2.15–2.35 (1H, m), 2.32 (3H,s), 3.66 (2H, bs), 4.19 (2H, d, J=7.8 Hz), 6.69 (1H, d, J=1.8 Hz),7.20–7.30 (3H, m), 7.45–7.55 (3H, m), 8.36 (1H, d, J=8.4 Hz).

(2)3-(Aminomethyl)-2-isobutyl-6-(methylsulfanyl)-4-phenyl-1(2H)-isoquinolinone(0.13 g, 0.37 mmol) was dissolved in ethyl acetate (3 mL) and a solution(1 mL) of 4N hydrogen chloride in ethyl acetate was added thereto. Themixture was stirred for 5 min and concentrated under reduced pressure.The obtained residue was crystallized from ethyl acetate-diisopropylether (1:2) to give the title compound (0.14 g, 95%) as colorlesscrystals.

Elemental analysis for C₂₁H₂₄N₂OS HCl, Calculated:C, 64.85; H, 6.48; N,7.20. Found: C, 64.79; H, 6.55; N, 6.99. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d,J=6.6 Hz), 1.95–2.20 (1H, m), 2.34 (3H, s), 3.86 (2H, bs), 4.00–4.15(2H, m), 6.59 (1H, d, J=1.8 Hz), 7.35–7.65 (6H, m), 8.23 (1H, d, J=8.4Hz), 8.46 (1H, bs), 8.58 (2H, bs). Melting point 252–255° C.

Example 1712-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]sulfanyl}acetamide

A solution (2 mL) of 2-mercaptoacetamide (0.27 g, 3.0 mmol) inN,N-dimethylformamide was ice-cooled under a nitrogen atmosphere andsodium hydride (0.12 g, 3.0 mmol) (60% in oil) was added thereto. Theresulting mixture was stirred under ice-cooling for 30 min. To theobtained suspension was added3-(aminomethyl)-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (1.06g, 2.74 mmol), and the mixture was stirred at 80° C. for 24 h. Thereaction mixture was partitioned between water (100 mL) and ethylacetate (50 mL), and the aqueous layer was extracted twice with ethylacetate (50 mL). The extracts were combined and washed with saturatedbrine (20 mL), dried over anhydrous magnesium sulfate (12 g) andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate:methanol=1:0–10:1 (v/v)) andrecrystallized from n-hexane-ethyl acetate (1:1) to give the titlecompound (0.54 g, 50%) as a colorless powder.

Elemental analysis for C₂₂H₂₅N₃O₂S, Calculated:C, 66.81; H, 6.37; N,10.62. Found: C, 66.40; H, 6.41; N, 10.26. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d,J=6.6 Hz), 2.20–2.30 (1H, m), 3.52 (2H, s), 3.66 (2H, bs), 4.19 (2H, d,J=7.4 Hz), 5.39 (1H, bs), 6.41 (1H, bs), 6.79 (1H, d, J=1.8 Hz),7.20–7.35 (3H, m), 7.45–7.55 (3H, m), 8.36 (1H, d, J=8.6 Hz). Meltingpoint 218–220° C.

Example 1723-(Aminomethyl)-2-isobutyl-6-(methylsulfinyl)-4-phenyl-1(2H)-isoquinolinone

To a mixture of3-(aminomethyl)-2-isobutyl-6-(methylsulfanyl)-4-phenyl-1(2H)-isoquinolinone(0.18 g, 0.52 mmol), conc. sulfuric acid (0.0168 mL, 0.31 mmol),methanol (2 mL) and water (5 mL) was added Oxone® (0.19 g, 0.31 mmol),and the mixture was stirred at room temperature for 30 min. The reactionmixture was poured into saturated, aqueous sodium hydrogencarbonate (50mL) and extracted 3 times with ethyl acetate (25 mL). The extracts werecombined, washed with saturated brine (10 mL), dried over anhydrousmagnesium sulfate (9 g) and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate:methanol=10:1 (v/v)). The resulting oil was solidified fromdiisopropyl ether (1 mL) to give the title compound (0.081 g, 42%) as apale-yellow powder.

Elemental analysis for C₂₁H₂₄N₂O₂S 2H₂O, Calculated:C, 62.35; H, 6.98;N, 6.93. Found: C, 62.27; H, 6.58; N, 6.36. ¹H-NMR(CDCl₃) δ: 1.01 (6H,d, J=6.6 Hz), 2.20–2.35 (1H, m), 2.66 (3H, s), 3.69 (2H, bs), 4.24 (2H,d, J=7.4 Hz), 7.20–7.35 (3H, m), 7.45–7.55 (3H, m), 7.64 (1H, dd, J=1.8,8.6 Hz), 8.63 (1H, d, J=8.6 Hz). Melting point 167° C. (decomposition)

Example 1733-(Aminomethyl)-2-isobutyl-6-(methylsulfonyl)-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) A mixture oftert-butyl(6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.24 g, 0.5 mmol), sodium thiomethoxide (0.080 g, 1.1 mmol) andN,N-dimethylformamide (4 mL) was stirred at 85° C. for 1 h, and thereaction mixture was poured into water (50 mL) and extracted twice withethyl acetate (25 mL). The extracts were combined, washed with saturatedaqueous sodium hydrogencarbonate (15 mL) and saturated brine (15 mL),dried over anhydrous magnesium sulfate (12 g) and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=4:1 (v/v)) to givetert-butyl[2-isobutyl-6-(methylsulfanyl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.17 g, 73%) as a colorless powder.

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.15–2.35 (1H,m), 2.32 (3H, s), 4.06 (2H, d, J=7.8 Hz), 4.19 (2H, d, J=6.0 Hz), 4.46(1H, br), 6.68 (1H, d, J=1.8 Hz), 7.20–7.35 (3H, m), 7.40–7.60 (3H, m),8.34 (1H, d, J=8.4 Hz).

(2) To a solution (5 mL) oftert-butyl[2-isobutyl-6-(methylsulfanyl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.17 g, 0.37 mmol) in dichloromethane was added m-chloroperbenzoic acid(0.13 g, 7.7 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 1 h. The reaction mixture was washed once with 5%aqueous sodium thiosulfate solution (15 mL) and twice with saturatedaqueous sodium hydrogencarbonate (15 mL), and partitioned using a PTFEtube. The organic layer was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=2:1 (v/v)) to givetert-butyl[2-isobutyl-6-(methylsulfonyl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.16 g, 93%) as a colorless oil.

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.15–2.35 (1H,m), 2.99 (3H, s), 4.12 (2H, d, J=6.9 Hz), 4.24 (2H, d, J=6.0 Hz), 4.42(1H, br), 7.30–7.35 (2H, m), 7.50–7.60 (4H, m), 7.94 (1H, dd, J=1.8, 8.4Hz), 8.66 (1H, d, J=8.4 Hz).

(3) A mixture oftert-butyl[2-isobutyl-6-(methylsulfonyl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.16 g, 0.33 mmol) and a solution (5 mL) of 4N hydrogen chloride inethyl acetate was stirred for 1 h and concentrated under reducedpressure. The obtained residue was precipitated from ethylacetate-diisopropyl ether (1:10) to give, the title compound (0.12 g,87%) as a colorless powder.

Elemental analysis for C₂₁H₂₄N₂O₃S HCl H₂O 0.25IPE, Calculated:C, 58.18;H, 6.62; N, 6.03. Found: C, 58.15; H, 6.87; N, 5.89. ¹H-NMR(DMSO-d₆) δ:0.93 (6H, d, J=6.6 Hz), 2.05–2.20 (1H, m), 3.22 (3H, s), 3.90 (2H, bs),4.11 (2H, bd, J=6.6 Hz), 7.40–7.50 (3H, m), 7.55–7.70 (3H, m), 8.09 (1H,dd, J=1.8, 8.4 Hz), 8.57 (1H, d, J=8.4 Hz), 8.60 (1H, br). Melting point209° C. (decomposition)

Example 1743-(Aminomethyl)-2-isobutyl-6-(methanesulfonylamino)-4-phenyl-1(2H)-isoquinolinonehydrochloride

This compound was synthesized according to the method similar to that inExample 88 from6-amino-3-(tert-butoxycarbonylaminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 111(1)).

¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 2.08 (1H, m), 2.98 (3H, s),3.85 (2H, s), 4.03 (2H, d, J=6.2 Hz), 6.75 (1H, d, J=1.8 Hz), 7.36–7.44(3H, m), 7.54–7.58 (3H, m), 7.77 (1H, d, J=8.8 Hz), 8.46 (3H, bs), 10.29(1H, bs).

Example 1753-(Aminomethyl)-2-isobutyl-6-(methoxycarbonylamino)-4-phenyl-1(2H)-isoquinolinonehydrochloride

This compound was synthesized according to the method similar to that inExample 88 from6-amino-3-(tert-butoxycarbonylaminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 111(1)).

¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 2.08 (1H, m), 3.59 (3H, s),3.85 (2H, s), 4.02 (2H, d, J=6.6 Hz), 7.22 (1H, d, J=1.8 Hz), 7.34–7.38(2H, m), 7.54–7.63 (5H, m), 8.23 (1H, d, J=8.8 Hz), 8.40 (3H, bs), 10.04(1H, s).

Example 1763-(Aminomethyl)-2-isobutyl-6-(dimethanesulfonylamino)-4-phenyl-1(2H)-isoquinolinonehydrochloride

This compound was synthesized according to the method similar to that inExample 88 from6-amino-3-(tert-butoxycarbonylaminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(synthesized according to the method similar to that in Example 111(1)).

¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.11 (1H, m), 3.34 (3H, s),3.44 (2H, s), 3.90 (2H, s), 4.08 (2H, d, J=7.4 Hz), 6.86 (1H, d, J=1.8Hz), 7.41–7.45 (2H, m), 7.57–7.60 (3H, m), 7.73 (1H, dd, J=8.4, 1.8 Hz),8.43 (1H, d, J=8.4 Hz), 8.44 (3H, bs).

Example 177N-{3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl}-N′-methylureahydrochloride

This compound was synthesized according to the method similar to that inExample 80 from3-(tert-butoxycarbonylaminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylicacid (synthesized according to the method similar to that in Example 108(1)).

¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 2.07 (1H, m), 2.56 (3H, s),3.81 (2H, s), 4.00 (2H, d, J=7.0 Hz), 6.17 (1H, bs), 6.98 (1H, d, J=2.0Hz), 7.34–7.38 (2H, m), 7.54–7.67 (4H, m), 8.17 (1H, d, J=8.8 Hz), 8.39(3H, bs), 9.13 (1H, s).

Example 178N-{3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl}-N′,N′-dimethylureahydrochloride

This compound was synthesized according to the method similar to that inExample 80 from3-(tert-butoxycarbonylaminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylicacid (synthesized according to the method similar to that in Example 108(1)).

¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 2.07 (1H, m), 2.86 (6H, s),3.81 (2H, s), 4.02 (2H, d, J=7.0 Hz), 7.13 (1H, s), 7.34–7.38 (2H, m),7.54–7.57 (3H, m), 7.69 (1H, d, J=8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.41(3H, bs), 8.68 (1H, s).

Example 179N-{3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl}ureahydrochloride

This compound was synthesized according to the method similar to that inExample 80 from3-(tert-butoxycarbonylaminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone-6-carboxylicacid (synthesized according to the method similar to that in Example 108(1)).

¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 2.07 (1H, m), 3.82 (2H, d,J=4.0 Hz), 4.02 (2H, d, J=7.2 Hz), 5.96 (1H, bs), 6.70 (1H, bs), 6.51(1H, d, J=1.8 Hz), 7.35–7.39 (2H, m), 7.51–7.59 (3H, m), 7.79 (1H, dd,J=8.8, 1.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.44 (3H, bs), 9.10 (1H, s).

Example 180(E)-3-[3-(Aminomethyl)-4-(4-fluorophenyl)-2isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride

(1) To a solution oftert-butyl[4-(4-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.00 g, 3.5 mmol) in N,N-dimethylformamide (30 ml) was added sodiumhydride (0.19 g, 4.8 mmol) (60% in oil), at 0° C., and the mixture wasstirred at 0° C. for 10 min. To the obtained mixture was addedN-phenyltrifluoromethanesulfonimide (1.71 g, 4.8 mmol) and the mixturewas stirred at room temperature for 3 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. After washing the extractwith water, the extract was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to givetert-butyl[4-(4-fluorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.02 g, 88.2%) as an oil.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.14–2.28 (1H,m), 4.07 (2H, d, J=7.6 Hz), 4.22 (2H, d, J=5.8 Hz), 4.47 (1H, bs), 6.80(1H, d, J=2.4 Hz), 7.22–7.44 (5H, m), 8.55 (1H, d, J=8.6 Hz).

(2) A suspension oftert-butyl[4-(4-fluorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.00 g, 3.5 mmol), butyl acrylate (0.76 ml, 5.3 mmol), sodiumhydrogencarbonate (0.45 g, 5.5 mmol), tetrabutylammonium chloride (0.11g, 0.4 mmol) and palladium acetate (90 mg, 0.4 mmol) inN,N-dimethylformamide (30 ml) was stirred with heating at 100° C. underan argon atmosphere for 24 h. The reaction mixture was poured into waterand extracted with ethyl acetate. After washing the extract with water,the extract was dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to give butyl(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenateas an amorphous.

¹H-NMR(CDCl₃) δ: 0.95 (3H, t, J=7.7 Hz), 1.00 (6H, d, J=6.6 Hz),1.34–1.47 ((11H, m), 1.62–1.72 (2H, m), 2.18–2.28 (1H, m), 4.06 (2H, d,J=7.8 Hz), 4.13–4.21 (4H, m), 4.50 (1H, bs), 6.39 (1H, d, J=16.5 Hz),6.98 (1H, d, J=1.6Hz), 7.19–7.27 (4H, m), 7.55 (1H, d, J=16.5 Hz), 7.62(1H, dd, J=1.6, 8.7 Hz), 8.44 (1H, d, J=8.7 Hz).

(3) To a solution of butyl(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate(0.56 g, 1 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) wasadded 1N sodium hydroxide (2 ml). The obtained mixture was stirred atroom temperature for 1 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-diisopropyl ether to give(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.36 g, 72.0%) as crystals.

Melting point 201–202° C. Elemental analysis for C₂₈H₃₁N₂O₅F 0.25H₂OCalculated: C, 67.39; H, 6.36; N, 5.61. Found: C, 67.69; H, 6.27; N,5.49. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.4 Hz), 1.49 (9H, s), 2.11–2.24(1H, m), 4.04 (2H, d, J=7.2 Hz), 4.13 (2H, d, J=3.0 Hz), 5.74 (1H, bs),6.28 (1H, d, J=16.4 Hz), 6.77 (1H, s), 7.21–7.34 (5H, m), 7.43 (1H, d,J=16.4 Hz), 8.22 (1H, d, J=8.2 Hz).

(4) A solution of(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-3-dimethylaminopropyl)carbodiimidehydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammoniumsalt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred atroom temperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide(09.13 g, 65.0%) as crystals.

Melting point 161–163° C. ¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.44(9H, s), 2.16–2.24 (1H, m), 4.07 (2H, d, J=7.4 Hz), 4.19 (2H, d, J=5.6Hz), 4.96 (1H, bs), 5.75 (1H, bs), 6.38 (1H, d, J=15.6 Hz), 6.94 (1H,s), 7.26–7.30 (2H, m), 7.40–7.56 (5H, m), 8.29 (1H, d, J=8.4 Hz).

(5)(E)-3-[3-[[(Tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.10 g, 0.2 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and, the mixture was stirred at room temperaturefor 2 h. The reaction mixture was concentrated under reduced pressure,and the residue was crystallized from ethyl acetate to give(E)-3-[3-(aminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1.2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride (0.08 g, 88.8%) as crystals.

Melting point 255–258° C. Elemental analysis for C₂₃H₂₅N₃O₂ClF 0.75H₂OCalculated: C, 62.30; H, 6.02; N, 9.48. Found: C, 61.90; H, 6.38; N,9.31. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 1.99–2.19 (1H, m), 3.86(2H, d, J=4.0 Hz), 4.08 (2H, d, J=7.0 Hz), 6.57 (1H, d, J=15.8 Hz), 7.00(1H, d, J=1.6 Hz), 7.18 (1H, bs), 7.32–7.51 (5H, m), 7.67 (1H, bs), 7.78(1H, dd, J=1.6, 8.4 Hz), 8.35 (1H, d, J=8.4 Hz), 8.61 (3H, bs).

Example 1812-[[3-(Aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride

(1) A mixture of methyl6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(9.24 g, 18 mmol), 4-methylphenylboronic acid (2.94 g, 21.6 mmol) andsodium carbonate (2.86 g, 27 mmol) in toluene (50 ml)-methanol (10ml)-water (10 ml) was stirred under an argon atmosphere at roomtemperature for 30 min. To the obtained mixture was addedtetrakis(triphenylphosphine)palladium (1.04 g, 1 mmol) and the mixturewas refluxed under heating under an argon, atmosphere for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.After washing the extract with water, the extract was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give methyl6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(6.91 g, 84.4%) as crystals.

Melting point 142.5–143° C. Elemental analysis for C₂₉H₂₉N₄ Calculated:C, 76.46; H, 6.42; N, 3.07. Found: C, 76.35; H, 6.40; N, 2.86.¹H-NMR(CDCl₃) δ: 0.92 (6H, d, J=6.6 Hz), 2.04–2.20 (1H, m), 2.43 (3H,s), 3.47 (3H, s), 3.93 (2H, d, J=7.6 Hz), 4.97 (2H, s), 6.65 (1H, d,J=22.6 Hz), 7.11–7.37 (10H, m), 8.42 (1H, d, J=8.8 Hz).

(2) To a suspension of methyl6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(6.83 g, 15 mmol) in methanol (50 ml) was added an aqueous solution (20ml) of lithium hydroxide monohydrate (1.89 g, 45 mmol). The obtainedmixture was refluxed under heating for 24 h. The reaction mixture waspoured into water, acidified with 1N hydrochloric acid and extractedwith ethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained crystals was recrystallized from ethyl acetate-diisopropylether to give6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-3-isoquinolinecarboxylic acid(5.78 g, 87.3%) as crystals.

Melting point 153–154° C. ¹H-NMR(CDCl₃) δ: 0.85 (6H, d, J=6.6 Hz),2.03–2.21 (1H, m), 2.42 (3H, s), 3.86 (2H, d, J=7.4 Hz), 4.13 (1H, bs),4.96 (2H, s), 6.61 (1H, d, J=2.4 Hz), 7.10 (1H, dd, J=2.4, 9.0 Hz),7.13–7.36 (9H, m), 8.28 (1H, d, J=9.0 Hz).

(3) To a mixed solution of6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (5.74 g, 13 mmol) in tetrahydrofuran (50 ml) were added oxalylchloride (1.4 ml, 15.6 mmol) and N,N-dimethylformamide (3 drops), andthe mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 ml) The obtained solution was addeddropwise to a suspension of sodium tetrahydroborate (1.72 g, 45.5 mmol)in 1,2-dimethoxyethane (50 ml) at 0° C. The obtained mixture was stirredat 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloricacid and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4-methylphenyl)-1-(2H)-isoquinolinone(4.41 g, 79.5%) as crystals.

Melting point 74–76° C. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz),2.16–2.26 (1H, m), 2.41 (1H, bs), 2.47 (3H, s), 4.17 (2H, d, J=7.5 Hz),4.43 (2H, s), 4.89 (2H, s), 6.39 (1H, d, J=2.4 Hz), 6.98 (1H, dd, J=2.4,8.8 Hz), 7.17 (2H, d, J=7.8 Hz), 7.23–7.34 (7H, m), 8.28 (1H, d, J=8.8Hz).

(4) To a suspension of6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone(4.28 g, 10 mmol) in toluene (50 ml) was added thionyl chloride (1.5 ml,20 mmol). The obtained mixture was refluxed under heating for 2 h. Thereaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone(4.26 g, 95.5%) as an oil.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 2.14–2.30 (1H, m), 2.47 (3H,s), 4.15 (2H, d, J=6.8 Hz), 4.39 (2H, s), 4.93 (2H, s), 6.45 (1H, d,J=2.6 Hz), 7.09–7.35 (10H, m), 8.40 (1H, d, J=8.8 Hz).

(5) A solution of6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone(4.24 g, 9.5 mmol) and potassium phthalimide (2.65 g, 14.3 mmol) inN,N-dimethylformamide (50 ml) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give2-[[6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(5.07 g, 96.0%) as crystals.

Melting point 158–159° C. Elemental analysis for C₃₆H₃₂N₂O₄ Calculated:C, 77.68; H, 5.79; N, 5.03. Found: C, 77.89; H, 5.91; N, 4.96.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.14–2.28 (1H, m), 2.38 (3H,s), 4.01 (2H, d, J=7.2 Hz), 4.78 (2H, s), 4.92 (2H, s), 6.41 (1H, d,J=2.6 Hz), 7.09 (1H, dd, J=2.6, 8.8 Hz), 7.12–7.19 (4H, m), 7.20–7.35(5H, m), 7.66–7.76 (4H, m), 8.38 (1H, d, J=8.8 Hz).

(6) To a suspension of2-[[6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(5.01 g, 9 mmol) in ethanol (50 ml) was added hydrazine monohydrate (1.3ml, 27 mmol). The obtained mixture was refluxed under heating for 1 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (50 ml) and di-t-butyl dicarbonate (3.1 ml, 13.5 mmol)was added thereto. The obtained mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-diisopropyl ether togivetert-butyl[6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]-methylcarbamate(4.48 g, 94.5%) as crystals.

Melting point 164–164.5° C. Elemental analysis for C₃₃H₃₈N₂O₄Calculated: C, 75.26; H, 7.27; N, 5.32. Found: C, 75.17; H, 7.39; N,5.17. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=7.0 Hz), 1.42 (9H, s), 2.13–2.27(1H, m), 2.46 (3H, s), 4.03 (2H, d, J=7.2 Hz), 4.18 (2H, d, J=5.4 Hz),4.48 (1H, bs), 4.92 (2H, s), 6.38 (1H, d, J=2.6 Hz), 7.05–7.11 (3H, m),7.22–7.35 (7H, m), 8.37 (1H, d, J=8.8 Hz).

(7) A suspension oftert-butyl[6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(4.21 g, 8 mmol) and 5% palladium carbon (2.0 g) in ethanol (20 ml) andtetrahydrofuran (20 ml) was stirred under a hydrogen atmosphere at roomtemperature for 2 h. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to givetert-butyl[6-hydroxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(3.28 g, 94.0%) as crystals.

Melting point 233–234° C. Elemental analysis for C₂₆H₃₂N₂O₄ Calculated:C, 71.53; H, 7.39; N, 6.42. Found: C, 71.35; H, 7.35; N, 6.22.¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.41 (9H, s), 2.12–2.26 (1H,m), 2.41 (3H, s), 4.02 (2H, d, J=7.4 Hz), 4.19 (2H, d, J=5.4 Hz), 4.46(1H, bs), 6.39 (1H, d, J=2.2 Hz), 7.04 (1H, dd, J=2.2, 8.8 Hz), 7.08(2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.73 (1H, bs), 8.28 (1H, d,J=8.8 Hz).

(8) A solution oftert-butyl[6-hydroxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.44 g, 1 mmol), 2-iodoacetamide (0.37 g, 2 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.30 ml, 2 mmol) inN,N-dimethylacetamide (10 ml) was stirred at 80° C. for 12 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.18 g, 36.7%) as crystals.

Melting point 239–239.5° C. Elemental analysis for C₂₈H₃₅N₃O₅Calculated: C, 68.13; H, 7.15; N, 8.51. Found: C, 67.77; H, 7.09; N,8.21. ¹H-NMR(CDCl₃), δ: 0.99 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.15–2.29(1H, m), 2.47 (3H, s), 4.05 (2H, d, J=7.6 Hz), 4.19 (2H, d, J=5.4 Hz),4.33 (2H, s), 4.48 (1H, bs), 5.69 (1H, bs), 6.34 (1H, d, J=2.6 Hz), 6.52(1H, bs), 7.04 (1H, dd, J=2.6, 9.0 Hz), 7.10 (2H, d, J=7.9 Hz), 7.31(2H, d, J=7.9 Hz), 8.42 (1H, d, J=9.0 Hz).

(9)Tert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 2 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized from ethylacetate-diisopropyl ether to give2-[[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 278–280° C. Elemental analysis for C₂₃H₂₈N₃O₃ 0.5H₂OCalculated: C, 62.93; H, 6.66; N, 9.57. Found: C, 62.97; H, 6.53; N,9.28. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.99–2.16 (1H, m), 2.43(3H, s), 3.86 (2H, s), 4.04 (2H, d, J=7.0 Hz), 4.36 (2H, s), 6.34 (1H,d, J=2.6 Hz), 7.19 (1H, dd, J=2.6, 8.8 Hz), 7.25 (2H, d, J=8.2 Hz), 7.35(1H, bs), 7.37 (2H, d, J=8.2 Hz), 7.57 (1H, bs), 8.27 (1H, d, J=8.8 Hz),8.48 (3H, s).

Example 1823-(Aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone-6-carboxamidehydrochloride

(1) To a solution oftert-butyl[6-hydroxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(Example 181(7)) (2.18 g, 5 mmol) in N,N-dimethylformamide (20 ml) wasadded sodium hydride (0.30 g, 8.3 mmol) (60% in oil) at 0° C. and themixture was stirred at 0° C. for 30 min. To the obtained mixture wasadded N-phenyltrifluoromethanesulfonimide (2.68 g, 8.3 mmol) and themixture was stirred at room temperature for 2 h. The reaction mixturewas poured into water and extracted with ethyl acetate. After washingthe extract with water, the extract was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[2-isobutyl-4-(4-methylphenyl)-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.85 g, 100%) as an oil.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.14–2.27 (1H,m), 2.47 (3H, s), 4.09 (2H, d, J=7.4 Hz), 4.24 (2H, d, J=5.8 Hz), 4.45(1H, t, J=2.6 Hz), 6.86 (1H, d, J=2.6 Hz), 7.12 (2H, d, J=8.2 Hz),7.13–7.40 (3H, m), 8.54 (1H, d, J=8.8 Hz).

(2) A mixture oftert-butyl[2-isobutyl-4-(4-methylphenyl)-1-oxo-6-trifluorbmethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.84 g, 5 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.14 g, 0.25mmol), triethylamine (0.77 ml, 5.5 mmol) and palladium acetate (56 mg,0.25 mmol) in tetrahydrofuran (20 ml)-methanol (20 ml) was stirred withheating at 100° C. under a carbon monoxide atmosphere at 5 atm for 1 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give methyl3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(2.11 g, 88.3%) as crystals.

Melting point 193–194.5° C. Elemental analysis for C₂₈H₃₄N₂O₅Calculated: C, 70.27; H, 7.16; N, 5.85. Found: C, 69.97; H, 7.22; N,5.71. ¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.17–2.32(1H, m), 2.47 (3H, s), 3.86 (3H, s), 4.09 (2H, d, J=7.4 Hz), 4.22 (2H,d, J=5.8 Hz), 4.54 (1H, bs), 7.13 (2H, d, J=7.8 Hz), 7.32 (2H, d, J=7.8Hz), 7.68 (1H, d, J=1.6 Hz), 8.02 (1H, dd, J=1.6, 8.2 Hz), 8.49 (1H, d,J=8.2 Hz).

(3) To a solution of methyl3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(1.91 g, 4 mmol) in tetrahydrofuran (10 ml)-methanol (10 ml) was added1N sodium hydroxide (8 ml) and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from tetrahydrofuran-isopropyl ether to give3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (1.67 g, 90.3%) as crystals.

Melting point 230–231° C. Elemental analysis for C₂₇H₃₂N₂O₅ Calculated:C, 69.81; H, 6.94; N, 6.03. Found: C, 69.45; H, 7.09; N, 5.67.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.49 (9H, s), 2.07–2.25 (1H,m), 2.48 (3H, s), 4.05 (2H, d, J=7.4 Hz), 4.18 (2H, d, J=4.4 Hz), 5.75(1H, bs), 7.21 (2H, d, J=7.8 Hz), 7.32 (2H, d, J=7.8 Hz), 7.48 (1H, s),7.79 (1H, d, J=8.2 Hz), 8.32 (1H, d, J=8.2 Hz).

(4) A solution of3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (0.92 g, 2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.77 g, 4 mmol) and 1-hydroxybenzotriazole ammonium salt(0.61 g, 4 mmol) in N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoqinolinecarboxamide(82 g, 89.1%) as crystals.

Melting point 225–226° C. ¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43(9H, s), 2.17–2.28 (1H, m), 246 (3H, s), 4.08 (2H, d, J=7.2 Hz), 4.22(2H, d, J=5.6 Hz), 4.52 (1H, bs), 5.62 (1H, bs), 6.00 (1H, bs), 7.12(2H, d, J=7.8 Hz), 7.32 (2H, d, J=7.8 Hz), 7.42 (1H, d, J=1.8 Hz), 7.78(1H, dd, J=1.8, 8.4 Hz), 8.49 (1H, d, J=8.4 Hz).

(5) A solution of3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(0.42 g, 0.9 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized from methanol-diethylether to give 3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone-6-carboxamide hydrochloride (0.34 g, 94.4%) ascrystals.

Melting point 286–288° C. Elemental analysis for C₂₂H₂₆N₃O₃Cl 1.25H₂OCalculated: C, 62.55; H, 6.80; N, 9.95. Found: C, 62.66; H, 6.93; N,9.99. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 2.02–2.16 (1H, m), 2.45(3H, s), 3.88 (2H, s), 4.08 (2H, d, J=7.4 Hz), 7.28 (2H, d, J=8.1 Hz),7.39 (2H, d, J=8.1 Hz), 7.46 (1H, d, J=1.6 Hz), 7.58 (1H, bs), 7.99 (1H,d, J=1.6, 8.2 Hz), 8.16 (1H, bs), 8.36 (1H, d, J=8.2 Hz), 8.49 (3H, bs).

Example 1833-(Aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone-6-carbonitrilehydrochloride

(1) A solution of3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(Example 3 (4)) (0.37 g, 0.8 mmol) and cyanuric chloride (0.44 g, 2.4mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas, purified by silica gel column chromatography to givetert-butyl[6-cyano-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.32 g, 91.4%) as crystals.

Melting point 156–157° C. Elemental analysis for C₂₇H₃₁N₃O₃ Calculated:C, 72.78; H, 7.01; N, 9.43. Found: C, 72.66; H, 7.16; N, 9.46.¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.14–2.29 (1H,m), 2.48 (3H, s), 4.09 (2H, d, J=7.6 Hz), 4.24 (2H, d, J=5.8 Hz), 4.45(1H, bs), 7.10 (2H, d, J=7.7 Hz), 7.31 (1H, d, J=1.4 Hz), 7.35 (2H, d,J=7.7 Hz), 7.63 (1H, dd, J=1.4, 8.2 Hz), 8.53 (1H, d, J=8.2 Hz).

(2)Tert-butyl[6-cyano-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.27 g, 0.6 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperature,for 1 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized from methanol-diethylether to give3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone-6-carbonitrilehydrochloride (0.22 g, 95.7%) as crystals.

Melting point 278–279° C. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz),1.99–2.16 (1H, m), 2.45 (3H, s), 3.90 (2H, s), 4.11 (2H, d, J=7.0 Hz),7.25 (1H, d, J=1.4 Hz), 7.31 (2H, d, J=7.9 Hz), 7.41 (2H, d, J=7.9 Hz),7.96 (1H, dd, J=1.4, 8.4 Hz), 8.47 (1H, d, J=8.4 Hz), 8.65 (3H, bs).

Example 184(E)-3-[3-(Aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride

(1) A suspension oftert-butyl[2-isobutyl-4-(4-methylphenyl)-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(Example 182 (1)) (1.42 g, 2.5 mmol), butyl acrylate (0.54 ml, 3.8mmol), sodium hydrogencarbonate (0.32 g, 3.81 mmol), tetrabutylammoniumchloride (83 mg, 0.3 mmol) and palladium acetate (67 mg, 0.3 mmol) inN,N-dimethylformamide (30 ml) was stirred with heating at 100° C. underan argon atmosphere for 20 h. The reaction mixture was poured into waterand extracted with ethyl acetate. After washing the extract with water,the extract was dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to give butyl(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate(0.56 g, 40.3%) as an amorphous.

¹H-NMR(CDCl₃) δ: 0.95 (3H, t, J=7.8 Hz), 1.00 (6H, d, J=6.6 Hz),1.35–1.47 (11H, m), 1.62–1.71 (2H, m), 2.18–2.29 (1H, m), 2.49 (3H, s),4.08 (2H, d, J=6.0 Hz), 4.18 (2H, t, J=6.6 Hz), 4.22 (2H, d, J=4.8 Hz),4.52 (1H, bs), 6.38 (1H, d, J=15.9 Hz), 7.04 (1H, d, J=1.0 Hz), 7.13(2H, d, J=8.1 Hz), 7.33 (2H, d, J=8.1 Hz), 7.55 (1H, d, J=15.9 Hz), 7.61(1H, dd, J=1.0, 8.4 Hz), 8.44 (1H, d, J=8.4 Hz).

(2) To a solution of butyl((E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate(0.50 g, 0.9 mmol) in tetrahydrofuran (10 ml)-methanol (10 ml) was added1N sodium hydroxide (2 ml). The obtained mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-diisopropyl ether to give(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.38 g, 84.4%) as crystals.

Melting point 171–173° C. Elemental analysis for C₂₉H₃₄N₂O₅ 0.25H₂OCalculated: C, 70.35; H, 7.02; N, 5.66. Found: C, 70.16; H, 6.94; N,5.49. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.48 (9H, s), 2.08–2.29(1H, m), 2.50 (3H, s), 4.05 (2H, d, J=6.3 Hz), 4.17 (2H, d, J=4.5 Hz),5.46 (1H, bs), 6.30 (1H, d, J=15.9 Hz), 6.88 (1H, s), 7.20 (2H, d, J=7.6Hz), 7.34 (2H, d, J=7.6 Hz), 7.41 (1H, d, J=8.6 Hz), 7.47 (1H, d, J=15.9Hz), 8.29 (1H, d, J=8.6 Hz).

(3) A solution of(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.25 g, 0.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.19 g, 1 mmol) and 1-hydroxybenzotriazole ammonium salt(0.15 g, 1 mmol) in N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give(E)-3-[3-[[(tert-butoxycarbonyl)-amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.21 g, 84.0%) as crystals.

Melting point 152–154° C. Elemental analysis for C₂₉H₃₅N₃O₄ 0.75H₂OCalculated: C, 69.23; H, 7.31; N, 8.35. Found: C, 69.58; H, 7.29; N,8.01. ¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.16–2.28(1H, m), 2.48 (3H, s), 4.07 (2H, d, J=7.4 Hz), 4.22 (2H, d, J=5.6 Hz),4.70 (1H, bs), 5.71 (2H, bs), 6.40 (1H, d, J=15.6 Hz), 7.00 (1H, s),7.12 (2H, d, J=7.8 Hz), 7.32 (2H, d, J=7.8 Hz), 7.44–7.54 (2H, m), 8.36(1H, d, J=8.4 Hz).

(4)(E)-3-[3-[[(Tert-butoxycarbonyl)amino]methyl-]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperature,for 1 h. The reaction mixture was concentrated under reduced pressure,and the residue was crystallized from ethyl acetate-diisopropyl ether togive(E)-3-[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride (0.12 g, 92.3%) as crystals.

Melting point 264–266° C. Elemental analysis for C₂₄H₂₈N₃O₂Cl 1.25H₂OCalculated: C, 64.28; H, 6.85; N, 9.37. Found: C, 64.37; H, 6.88; N,9.08. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 2.04–2.16 (1H, m), 3.87(2 H, d, J=2.4 Hz), 4.08 (2H, d, J=6.9 Hz), 6.56 (1H, d, J=15.9 Hz),7.00 (1H, d, J=1.2 Hz), 7.18 (1H, bs), 7.25–7.42 (5H, m), 7.67 (1H, bs),7.77 (1H, dd, J=1.2, 8.7 Hz), 8.34 (1H, d, J=8.7 Hz), 8.53 (3H, bs).

Example 1852-[[3-(Aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride

(1) A mixed solution of methyl6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(10.27 g, 20 mmol), 4-chlorophenylboronic acid (3.75 g, 24 mmol) andsodium carbonate (5.30 g, 50 mmol) in toluene (50 ml)-methanol (10ml)-water (10 ml) was stirred under an argon atmosphere at roomtemperature for 30 min. To the obtained mixture was addedtetrakis(triphenylphosphine)palladium (1.15 g, 1 mmol) and the mixturewas refluxed under heating under an argon atmosphere for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.After washing the extract with water, the extract was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give methyl6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(5.21 g, 54.8%) as crystals.

Melting point 165.5–166° C. Elemental analysis for C₂₈H₂₆NO₄ClCalculated: C, 70.66; H, 5.51; N, 2.94 Found: C, 70.89; H, 5.68; N,2.78. ¹H-NMR(CDCl₃) δ: 0.91 (6H, d, J=7.0 Hz), 2.03–2.21 (1H, m), 3.50(3H, s), 3.93 (2H, d, J=7.8 Hz), 4.99 (2H, s), 6.52 (1H, d, J=2.6 Hz),7.15–7.22 (3H, m), 7.26–7.44 (7H, m), 8.42 (1H, d, J=8.8 Hz).

(2) To a suspension of methyl6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(5.00 g, 10.5 mmol) in 1,4-dioxane (50 ml) was added an aqueous solution(20 ml) of lithium hydroxide monohydrate (1.32 g, 31.5 mmol). Theobtained mixture was refluxed under heating for 24 h. The reactionmixture was poured into water, acidified with 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained, crystals were recrystallized fromtetrahydrofuran-n-hexane to give6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (4.69 g, 96.7%) as crystals.

Melting point 200–201° C. Elemental analysis for C₂₇H₂₄NO₄Cl Calculated:C, 70.20; H, 5.24; N, 3.03. Found: C, 70.12; H, 5.28; N, 2.97.¹H-NMR(CDCl₃) δ: 0.86 (6H, d, J=6.6 Hz), 2.07–2.25 (1H, m), 3.90 (2H, d,J=7.2 Hz), 5.00 (2H, s), 6.51 (1H, d, J=2.4 Hz), 7.14 (1H, dd, J=2.4,9.0 Hz), 7.21–7.40 (9H, m), 8.25 (1H, d, J=9.0 Hz).

(3) To a mixture of6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylicacid (4.62 g, 10 mmol) and tetrahydrofuran (50 ml) were added oxalylchloride (1.0 ml, 15.6 mmol) and N,N-dimethylformamide (3 drops), andthe mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 ml). The obtained solution was addeddropwise to a suspension of sodium tetrahydroborate (1.32 g, 35 mmol) in1,2-dimethoxyethane (30 ml) at 0° C. The obtained mixture was stirred at0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give6-benzyloxy-4-(4-chlorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(4.31 g, 96.4%) as crystals.

Melting point 87–88° C.

¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 2.11–2.28 (1H, m), 2.39 (1H,bs), 4.16 (2H, d, J=7.6 Hz), 4.41 (2H, d, J=5.4 Hz), 4.92 (2H, s), 6.29(1H, d, J=2.4 Hz), 7.00 (1H, dd, J=2.4, 9.0 Hz), 7.21–7.38 (7H, m), 7.45(2H, d, J=8.4 Hz), 8.27 (1H, d, J=8.8 Hz).

(4) To a suspension of6-benzyloxy-4-(4-chlorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone(4.25 g, 9.5 mmol) in toluene (50 ml) was added thionyl chloride (1.4ml, 19 mmol). The obtained mixture was refluxed under heating for 2 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give6-benzyloxy-3-chloromethyl-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone(3.98 g, 89.8%) as an oil.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 2.13–2.30 (1H, m), 4.14 (2H, d,J=7.6 Hz), 4.34 (2H, s), 4.96 (2H, s), 6.34 (1H, d, J=2.2 Hz), 7.06–7.38(8H, m), 7.44–7.50 (2H, m), 8.41 (1H, d, J=8.8 Hz).

(5) A solution of6-benzyloxy-3-chloromethyl-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone(3.96 g, 8.5 mmol) and potassium phthalimide (2.37 g, 12.8 mmol) inN,N-dimethylformamide (40 ml) was stirred at room temperature for 6 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give2-[[6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(4.72 g, 96.3%) as crystals.

Melting point 182–183° C. Elemental analysis for C₃₅H₂₉N₂O₄ClCalculated: C, 72.85; H, 5.07; N, 4.85. Found: C, 72.95; H, 5.19; N,4.70. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.09–2.31 (1H, m), 4.00(2H, d, J=7.2 Hz), 4.74 (2H, s), 4.93 (2H, s), 6.29 (1H, d, J=2.6 Hz),7.11 (1H, dd, J=2.6, 8.8 Hz), 7.19–7.41 (9H, m), 7.66–7.79 (4H, m), 8.38(1H, d, J=8.8 Hz).

(6) To a suspension of2-[[6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione(4.61 g, 8 mmol) in ethanol (50 ml) was added hydrazine monohydrate (1.2ml, 24 mmol). The obtained mixture was refluxed under heating for 1 h.The reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (50 ml) and di-t-butyl dicarbonate (2.8 ml, 12 mmol) wasadded thereto. The obtained mixture was stirred at room temperature for1 h. The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from ethyl acetate-diisopropyl ether togivetert-butyl[6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(4.16 g, 95.2%) as crystals.

Melting point 186–187° C. Elemental analysis for C₃₂H₃₅N₂O₄ClCalculated: C, 70.25; H, 6.45; N, 5.12. Found: C, 70.17; H, 6.43; N,5.00. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.14–2.28(1H, m), 4.02 (2H, d, J=7.6 Hz), 4.15 (2H, d, J=5.2 Hz), 4.46 (1H, bs),4.95 (2H, s), 6.28 (1H, d, J=2.6 Hz), 7.07–7.16 (3H, m), 7.22–7.37 (5H,m), 7.42–7.49 (2H, m), 8.37 (1H, d, J=8.8 Hz).

(7)Tert-butyl[6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.54 g, 1 mmol) was suspended in 48% aqueous solution (20 ml) ofhydrogen bromide and the obtained mixture was refluxed under heating for3 h. The reaction mixture was neutralized with 1N sodium hydroxideaqueous solution and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (10 ml) and di-t-butyl dicarbonate (0.28 ml, 1 mmol) wasadded thereto. The obtained mixture was stirred at room temperature for1 h. The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl[4-(4-chlorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.32 g, 71.1%) as crystals.

Melting point 220–221° C. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.42(9H, s), 2.08–2.29 (1H, m), 4.01 (2H, d, J=7.0 Hz), 4.13 (2H, d, J=5.6Hz), 4.50 (1H, bs), 6.33 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 8.8Hz), 7.03 (2H, d, J=8.2 Hz), 7.40 (2H, d, J=8.2 Hz), 7.93 (1H, bs), 8.26(1H, d, J=8.8 Hz).

(8) To a solution oftert-butyl[4-(4-chlorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.45 g, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodiumhydride (48 mg, 1.2 mmol) (60% in oil) at 0° C., and the mixture wasstirred at 0° C. for 10 min. To the obtained mixture was added2-iodoacetamide (0.22 g, 1.2 mmol) and the mixture was stirred at 0° C.for 2 h. The reaction mixture was poured into water and extracted withethyl acetate. After washing the extract with water, the extract wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto givetert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.27 g, 52.9%) as crystals.

Melting point 241–242° C. Elemental analysis for C₂₇H₃₂N₃O₅ClCalculated: C, 63.09; H, 6.27; N, 8.17. Found: C, 63.07; H, 6.32; N,8.22. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.10–2.28(1H, m), 4.04 (2H, d, J=7.4 Hz), 4.17 (2H, d, J=5.4 Hz), 4.35 (2H, s),4.56 (1H, bs), 5.79 (1H, bs), 6.28 (1H, d, J=2.4 Hz), 6.50 (1H, bs),7.04 (1H, dd, J=2.4, 9.0 Hz), 7.17–7.24 (2H, m), 7.47–7.53 (2H, m), 8.41(1H, d, J=9.0 Hz).

(9)Tert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.20 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 2 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized from ethylacetate-diisopropyl ether to give2-[[3-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamidehydrochloride (0.16 g, 88.9%) as crystals.

Melting point 260–262° C. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz),1.99–2.18 (1H, m) 3.84 (2H, bs), 4.03 (2H, d, J=7.4 Hz), 4.39 (2H, s),6.31 (1H, d, J=2.4 Hz), 7.21 (1H, dd, J=2.4, 9.0 Hz), 7.36 (1H, bs),7.40 (2H, d, J=8.4 Hz), 7.59 (1H, bs), 7.62 (2H, d, J=8.4 Hz), 8.27 (1H,d, J=9.0 Hz), 8.51 (3H, s).

Example 1863-(Aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride

(1) To a solution oftert-butyl[6-hydroxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(Example 185(7)) (1.83 g, 4 mmol) in N,N-dimethylformamide (20 ml) wasadded sodium hydride (0.24 g, 6 mmol) (60% in oil) at 0° C., and themixture was stirred at 0° C. for 10 min. To the obtained mixture wasadded N-phenyltrifluoromethanesulfonimide (2.14 g, 6 mmol) and themixture was stirred at room temperature for 2 h. The reaction mixturewas poured into water and extracted with ethyl acetate. After washingthe extract with water, the extract was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[4-(4-chlorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.36 g, 100%) as an oil.

¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.04–2.26 (1H,m), 4.07 (2H, d, J=7.4 Hz), 4.21 (2H, d, J=5.4 Hz), 4.50 (1H, bs), 6.81(1H, d, J=2.6 Hz), 7.17–7.26 (2H, m), 7.50–7.57 (3H, m), 8.54 (1H, d,J=8.8 Hz).

(2) A mixed solution oftert-butyl[4-(4-chlorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.35 g, 4 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.11 g, 0.2mmol), triethylamine (0.6 ml, 4.4 mmol) and palladium acetate (45 mg,0.2 mmol) in tetrahydrofuran (20 ml)-methanol (20 ml) was stirred withheating at 100° C. under a carbon monoxide atmosphere at 5 atm for 2 h.The reaction mixture was poured into water and extracted with ethylacetate. After washing the extract with water, the extract was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give methyl3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate(1.71 g, 85.9%) as crystals.

Melting point 205–207° C. Elemental analysis for C₂₇H₃₁N₂O₅ClCalculated: C, 64.99; H, 6.26; N, 5.61. Found: C, 64.91; H, 6.44; N,5.34. ¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.14–2.30(1H, m), 3.87 (3H, s), 4.08 (2H, d, J=7.2 Hz), 4.20 (2H, d, J=5.6 Hz),4.55 (1H, bs), 7.19–7.25 (2H, m), 7.49–7.56 (2H, m), 7.61 (1H, d, J=1.5Hz), 8.03 (1H, dd, J=1.5, 8.5 Hz), 8.49 (1H, d, J=8.5 Hz).

(3) To a solution of methyl3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinonecarboxylate(1.50 g, 3 mmol) in tetrahydrofuran (10 ml)-methanol (10 ml) was added1N sodium hydroxide (6 ml) and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from tetrahydrofuran-isopropyl ether to give3-[[((tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (1.41 g, 97.2%) as crystals.

Melting point 226–227° C. Elemental analysis for C₂₆H₂₉N₂O₅ClCalculated: C, 64.39; H, 6.03; N, 5.78. Found: C, 64.50; H, 6.36; N,5.37. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.49 (9H, s), 2.10–2.26(1H, m), 4.04 (2H, d, J=6.6 Hz), 4.14 (2H, s), 5.65 (1H, bs), 7.29 (2H,d, J=8.2 Hz), 7.44 (1H, s), 7.52 (2H, d, J=8.2 Hz), 7.83 (1H, d, J=8.0Hz), 8.32 (1H, d, J=8.0 Hz).

(4) A solution of3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (1.21 g, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.96 g, 5 mmol) and 1-hydroxybenzotriazole ammonium salt(0.76 g, 5 mmol) in N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized from ethylacetate-diisopropyl ether to give3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(1.02 g, 85.0%) as crystals.

Melting point 144–146° C. Elemental analysis for C₂₆H₃₀N₃O₄Cl 0.25H₂OCalculated: C, 63.93; H, 6.29; N, 8.60. Found: C, 64.06; H, 6.06; N,8.53. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.45 (9H, s), 2.14–2.26(1H, m), 4.06 (2H, d, J=6.9 Hz), 4.18 (2H, d, J=4.5 Hz), 4.92 (1H, bs),5.89 (1H, bs), 6.22 (1H, bs), 7.24 (2H, d, J=8.4 Hz), 7.35 (1H, d, J=1.2Hz), 7.50 (2H, d, J=8.4 Hz), 7.66 (1H, dd, J=1.2, 8.4 Hz), 8.35 (1H, d,J=8.4 Hz).

(5)3-[[(Tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(0.48 g, 1 mmol) was dissolved in a solution of 4N hydrogen chloride inethyl acetate (5 ml) and the mixture was stirred at room temperature for1 h. The reaction mixture was concentrated under reduced pressure, andthe precipitated crystals were recrystallized from methanol-diethylether to give3-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carboxamidehydrochloride (0.41 g, 97.6%) as crystals.

Melting point 260–261° C. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz),1.99–2.17 (1H, m), 3.85 (2H, s), 4.08 (2H, d, J=7.0 Hz), 7.44 (2H, d,J=8.0 Hz), 7.45 (1H, d, J=1.5 Hz), 7.60 (1H, bs), 7.64 (2H, d, J=8.0Hz), 8.01 (1H, d, J=1.5, 8.4 Hz), 8.19 (1H, bs), 8.38 (1H, d, J=8.4 Hz),8.56 (3H, bs).

Example 1873-(Aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carbonitrilehydrochloride

(1) A solution of3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(Example 186 (4)) (0.48 g, 1 mmol) and cyanuric chloride (0.55 g, 3mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl[4-(4-chlorophenyl)-6-cyano-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.37 g, 80.4%) as crystals.

Melting point 234–235° C. Elemental analysis C₂₆H₂₈N₃O₃Cl Calculated: C,67.02; H, 6.06; N, 9.02. Found: C, 67.10; H, 6.09; N, 9.07.¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.16–2.30 (1H,m), 4.08 (2H, d, J=7.4 Hz), 4.22 (2H, d, J=5.8 Hz), 4.44 (1H, bs),7.16–7.23 (2H, m), 7.26 (1H, d, J=1.6 Hz), 7.51–7.58 (2H, m), 7.65 (1H,dd, J=1.6, 8.6 Hz), 8.55 (1H, d, J=8.6 Hz).

(2)Tert-butyl[4-(4-chlorophenyl)-6-cyano-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.28 g, 0.6 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized from methanol-diethylether to give3-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone-6-carbonitrilehydrochloride (0.23 g, 95.8%) as crystals.

Melting point 280–281° C. Elemental analysis for C₂₁H₂₁N₃OCl Calculated:C, 62.69; H, 5.26; N, 10.44. Found: 62.34; H, 5.31; N, 10.45.¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 1.99–2.19 (1H, m), 3.87 (2H,s), 4.10 (2H, d, J=7.4 Hz), 7.32 (1H, d, J=1.4 Hz), 7.43–7.49 (2H, m),7.64–7.68 (2H, m), 7.97 (1H, dd, J=1.4, 8.4 Hz), 8.47 (1H, d, J=8.4 Hz),8.67 (3H, bs).

Example 188(E)-3-[3-(Aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride

(1) A suspension oftert-butyl[4-(4-chlorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(Example 186 (1)) (2.06 g, 3.5 mmol), butyl acrylate (0.76 ml, 5.3mmol), sodium hydrogencarbonate (0.45 g, 5.3 mmol), tetrabutylammoniumchloride (0.11 g, 0.4 mmol) and palladium acetate (0.09 g, 0.4 mmol) inN,N-dimethylformamide (20 ml) was stirred with heating at 100° C. underan argon atmosphere for 48 h. The reaction mixture was poured into waterand extracted with ethyl acetate. After washing the extract with water,the extract was dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to give butyl(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate(0.48 g, 23.8%) as crystals.

Melting point 149–150° C. Elemental analysis for C₃₂H₃₉N₂O₅Cl 0.25H₂OCalculated: C, 67.24; H, 6.97; N, 4.90. Found: C, 67.22; H, 7.01; N,4.93. ¹H-NMR(CDCl₃) δ: 0.95 (3H, t, J=7.4 Hz), 1.00 (6H, d, J=6.4 Hz),1.32–1.50 (11H, m), 1.59–1.71 (2H, m), 2.14–2.30 (1H, m), 4.07 (2H, d,J=7.6 Hz), 4.16–4.22 (4H, m), 4.43 (1H, bs), 6.40 (1H, d, J=16.2 Hz),6.98 (1H, d, J=1.4 Hz), 7.20 (2H, d, J=8.4 Hz), 7.52 (2H, d, J=8.4 Hz),7.55 (1H, d, J=16.2 Hz), 7.63 (1H, dd, J=1.4, 8.4 Hz), 8.45 (1H, d,J=8.4 Hz).

(2) To a solution of butyl(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate(0.41 g, 0.7 mmol) in tetrahydrofuran (10 ml)-methanol (10 ml) was added1N sodium hydroxide (2 ml) and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into water,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained crystalswere recrystallized from ethyl acetate-diisopropyl ether to give(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.34 g, 91.9%) as crystals.

Melting point 147–149° C. Elemental analysis for C₂₈H₃₁N₂O₅Cl 0.25H₂OCalculated: C, 65.24; H, 6.16; N, 5.43. Found: C, 65.18; H, 6.15; N,5.31. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.4 Hz), 1.48 (9H, s), 2.08–2.28(1H, m), 4.05 (2H, d, J=5.8 Hz), 4.14 (2H, s), 5.46 (1H, bs), 6.32 (1H,d, J=15.8 Hz), 6.82 (1H, s), 7.26–7.31 (2H, m), 7.42–7.56 (4H, m), 8.28(1H, d, J=7.8 Hz).

(3) A solution of(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenicacid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammoniumsalt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred atroom temperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-n-hexane togive(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.18 g, 90.0%) as crystals.

Melting point 152–154° C. Elemental analysis for C₂₈H₃₂N₃O₄Cl 0.25H₂OCalculated: C, 65.36; H, 6.37; N, 8.17. Found: C, 65.30; H, 6.27; N,7.99. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.45 (9H, s), 2.12–2.28(1H, m), 4.05 (2H, d, J=7.2 Hz), 4.18 (2H, d, J=4.6 Hz), 4.95 (1H, bs),5.72 (1H, bs), 5.85 (1H, bs), 6.37 (1H, d, J=15.8 Hz), 6.91 (1H, d,J=1.2 Hz), 7.24 (2H, d, J=8.8 Hz), 7.41–7.54 (4H, m), 8.28 (1H, d, J=8.4Hz).

(4) A solution of(E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide(0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room,temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the residue was crystallized from ethyl acetate to give(E)-3-[3-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamidehydrochloride (0.12 g, 92.3%) as crystals.

Melting point 261–263° C. Elemental analysis for C₂₃H₂₅N₃O₂Cl₂ 0.75H₂OCalculated: C, 60.07; H, 5.81; N, 9.14. Found: C, 59.78; H, 6.14; N,8.75. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 1.91–2.21 (1H, m), 3.85(2H, s), 4.06 (2H, d, J=7.4 Hz), 6.58 (1H, d, J=15.8 Hz), 7.02 (1H, s),7.19 (1H, bs), 7.34–7.47 (3H, m), 7.62–7.67 (3H, m), 7.79 (1H, d, J=8.0Hz,) 8.35 (1H, d, J=8.0 Hz), 8.60 (3H, bs).

Example 1893-(Aminomethyl)-4-butoxy-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1(2H)-isoquinolinonedihydroxhloride

(1) To a suspension of3-[[(tert-butoxycarbonyl)amino]methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(0.44 g, 1 mmol) in toluene (20 ml) was added Lawesson's reagent (0.24g, 0.6 mmol), and the mixture was refluxed under heating for 1 h. Thereaction mixture was purified by silica gel column chromatography togivetert-butyl[6-(aminothiocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.18 g, 39.1%) as crystals.

Melting point 189–190° C. Elemental analysis for C₂₄H₃₅N₃O₄S Calculated:C, 62.44; H, 7.64; N, 9.10. Found: C, 62.38; H, 7.51; N, 8.89.¹H-NMR(CDCl₃) δ: 0.93 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.3 Hz),1.50–1.64 (11H, m), 1.80–1.93 (2H, m), 2.04–2.18 (1H, m), 3.83 (2H, t,J=6.8 Hz), 3.96 (2H, d, J=7.4 Hz), 4.48 (2H, d, J=5.6 Hz), 5.37 (1H,bs), 7.67 (1H, d, J=8.3 Hz), 7.83–7.90 (2H, m), 8.05 (1H, d, J=8.3 Hz),8.31 (1H, bs).

(2) A suspension oftert-butyl[6-(aminothiocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.46 g, 1 mmol), bromoacetone (0.20 g, 1.5 mmol) and sodium acetate(0.12 g, 1.5 mmol) in ethanol (10 ml) was refluxed under heating for 12h. The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl[4-butoxy-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.36 g, 73.5%) as an amorphous.

Elemental analysis for C₂₇H₃₇N₃O₄S Calculated: C, 64.90; H, 7.46; N,8.41. Found: C, 64.63; H, 7.58; N, 8.26. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d,J=7.0 Hz), 1.07 (3H, t, J=7.3 Hz), 1.47 (9H, s), 1.56–1.75 (2H, m),1.84–1.98 (2H, m), 2.12–2.26 (1H, m), 2.55 (3H, d, J=0.8 Hz), 3.92 (2H,t, J=6.4 Hz), 4.00 (2H, d, J=7.4 Hz), 4.54 (2H, d, J=5.8 Hz), 4.78 (1H,bs), 6.98 (1H, q, J=0.8 Hz), 8.08 (1H, dd, J=1.8, 8.4 Hz), 8.22 (1H, d,J=1.8 Hz), 8.46 (1H, d, J=8.4 Hz).

(3)Tert-butyl[4-butoxy-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.30 g, 0.6 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized frommethanol-diisopropyl ether to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1(2H)-isoquinolinonedihydrochloride (0.27 g, 96.4%) as crystals.

Melting point 201–202° C. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz),1.04 (3H, t, J=7.1 Hz), 1.56–1.74 (2H, m), 1.82–2.12 (3H, m), 2.48 (3H,d, J=0.6 Hz), 3.98–4.02 (4H, m), 4.21 (2H, d, J=5.2 Hz), 7.51 (1H, q,J=0.6 Hz), 8.13 (1H, dd, J=1.6, 8.4 Hz), 8.25 (1H, d, J=1.6 Hz), 8.37(1H, d, J=8.4 Hz), 8.76 (3H, bs).

Example 190 Ethyl2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylatehydrochloride

(1)Tert-butyl[6-(aminothiocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(Example 189 (1)) (1.38 g, 3 mmol) was dissolved in a solution of 4Nhydrogen chloride in ethyl acetate (10 ml) and the mixture was stirredat room temperature for 1 h. The reaction mixture was concentrated underreduced pressure and the residue was suspended in tetrahydrofuran (20ml). To the obtained mixture were added triethylamine (0.84 ml, 6 mmol)and 9-fluorenylmethylchloroformate (1.16 g, 4.5 mmol) and the mixturewas stirred at 0° C. for 1 h. The reaction mixture was poured into waterand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(1.52 g, 86.9%) as an amorphous.

¹H-NMR(CDCl₃) δ: 0.94–1.00 (9H, m), 1.47–1.59 (2H, m), 1.74–1.83 (2H,m), 2.07–2.18 (1H, m), 3.77 (2H, t, J=6.3 Hz), 3.98 (2H, d, J=6.6 Hz),4.25 (1H, t, J=6.6 Hz), 4.51–4.53 (4H, m), 5.79 (1H, bs), 7.26–7.41 (4H,m), 7.63–7.66 (3H, m), 7.75 (2H, d, J=7.2 Hz), 7.86 (1H, bs), 7.93 (1H,s), 8.00 (1H,bs), 8.12 (1H, d, J=8.1 Hz).

(2) A solution of9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.29 g, 0.5 mmol) and ethyl bromopyruvate (0.19 g, 1 mmol) in ethanol(10 ml) was refluxed under heating for 1 h. The reaction mixture waspoured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was crystallized fromethyl acetate-diisopropyl ether to give ethyl2-[4-butoxy-3-[[[(9H-fluoren-9-ylmethoxy)carbony]amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(0.30 g, 90.9%) as crystals.

Melting point 203–203.5° C. Elemental analysis for C₃₉H₄₁N₃O₆SCalculated: C, 68.90; H, 6.08; N, 6.18. Found: C, 68.64; H, 6.10; N,6.06. ¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 1.07 (3H, t, J=7.1 Hz),1.45 (3H, t, J=7.0 Hz), 1.56–1.75 (2H, m), 1.81–1.98 (2H, m), 2.06–2.24(1H, m), 3.94 (2H, t, J=6.4 Hz), 4.05 (2H, d, J=7.0 Hz), 4.22 (1H, t,J=6.6 Hz), 4.47 (2H, q, J=7.0 Hz), 4.49 (2H, d, J=6.6 Hz), 4.59 (2H, d,J=5.4 Hz), 5.23 (1H, bs), 7.29–7.43 (4H, m), 7.59 (2H, d, J=7.3 Hz),8.14 (1H, dd, J=1.6, 8.4 Hz), 8.24–8.26 (2H, m), 8.47 (1H, d, J=8.4 Hz).

(3) To a solution of ethyl2-[4-butoxy-3-[[[(9H-fluoren-9-ylmethoxy)carbony]amino]ethyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(1.70 g, 2.5 mmol) in N,N-dimethylformamide (25 ml)-tetrahydrofuran (25ml) was added pyrrolidine (2 ml), and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (20 ml) anddi-t-butyl dicarbonate (0.89 ml, 4 mmol) was added thereto. The obtainedmixture was stirred at room temperature for 1 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give ethyl2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(1.21 g, 87.1%) as crystals.

Melting point 172–172.5° C. Elemental analysis for C₂₉H₃₉N₃O₆SCalculated: C, 62.45; H, 7.05; N, 7.53. Found: C, 62.50; H, 7.04; N,7.53. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.07 (3H, t, J=7.3 Hz),1.45 (3H, t, J=7.2 Hz), 1.47 (9H, s), 1.62–1.78 (2H, m), 1.85–1.99 (2H,m), 2.12–2.26 (1H, m), 3.93 (2H, t, J=6.4 Hz), 4.01 (2H, d, J=7.2 Hz),4.47 (2H, q, J=7.2 Hz), 4.54 (2H, d, J=6.6 Hz), 4.77 (1H, bs), 8.16 (1H,dd, J=1.8, 8.4 Hz), 8.25 (1H, s), 8.28 (1H, d, J=1.8 Hz), 8.49 (1H, d,J=8.4 Hz).

(4)Ethyl2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(0.17 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml), and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized from ethylacetate-diisopropyl ether to give ethyl2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6isoquinolinyl]-1,3-thiazole-4-carboxylatehydrochloride (0.13 g, 92.9%) as crystals.

Melting point 224–226° C. Elemental analysis for C₂₄H₃₂N₃O₄ClS H₂OCalculated: C, 56.29; H, 6.69; N, 8.21. Found: C, 56.00; H, 6.43; N,7.99. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz),1.05 (3H, t, J=7.1 Hz),1.36 (3H, t, J=7.2 Hz), 1.57–1.76 (2H, m), 1.83–2.16 (3H, m), 3.98–4.06(4H, m), 4.22 (2H, d, J=4.6 Hz), 4.37 (2H, q, J=7.2 Hz), 8.20 (1H, ddJ=1.4, 8.4 Hz), 8.31 (1H, d, J=1.4 Hz), 8.42 (1H, d, J=8.4 Hz), 8.66(3H, bs), 8.73 (1H, s).

Example 1912-[3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carbocylicacid hydrochloride

(1) To a solution of ethyl2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(1.12 g, 2 mmol) in tetrahydrofuran (10 ml)-ethanol (5 ml) was added 1Nsodium hydroxide (4 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water, acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained crystals wererecrystallized from ethyl acetate-diisopropyl ether to give2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylicacid (0.97 g, 92.4%) as crystals.

Melting point 195–196° C. Elemental analysis for C₂₇H₃₅N₃O₆S Calculated:C, 61.23; H, 6.66; N, 7.93. Found: C, 61.10; H, 6.71; N, 7.65.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=7.0 Hz), 1.08 (3H, t, J=7.4 Hz), 1.48(9H, s), 1.57–1.76 (2H, m), 1.85–1.99 (2H, m), 2.13–2.26 (1H, m), 3.93(2H, t, J=6.2 Hz), 4.02 (2H, d, J=7.2 Hz), 4.56 (2H, d, J=5.6 Hz), 4.92(1H, bs), 8.11 (1H, dd, J=1.8, 8.4 Hz), 8.24 (1H, d, J=1.8 Hz), 8.36(1H, s), 8.49 (1H, d, J=8.4 Hz).

(2)2-[4-Butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylicacid (0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogenchloride in ethyl acetate (5 ml) and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was concentrated under reducedpressure and the residue was crystallized from ethyl acetate to give2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylicacid hydrochloride (0.13 g, 92.9%) as crystals.

Melting point 244–246° C. Elemental analysis for C₂₂H₂₈N₃O₄ClS 0.5H₂OCalculated: C, 55.63; H, 6.15; N, 8.85. Found: C, 55.45; H, 6.49; N,8.51. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.2 Hz),1.60–1.72 (2H, m), 1.84–1.93 (2H, m), 2.00–2.10 (1H, m), 3.99–4.02 (4H,m), 4.22 (2H, s), 8.21 (1H, dd, J=1.5, 8.4 Hz), 8.30 (1H, d, J=1.5 Hz),8.42 (1H, d, J=8.4 Hz), 8.63 (3H, bs), 8.66 (1H, s).

Example 1922-[3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxamidehydrochloride

(1) A solution of2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylicacid (0.79 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt(0.46 g, 3 mmol) in N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give tert-butyl[6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.74 g, 93.7%) as crystals.

Melting point 195–196° C. Elemental analysis for C₂₇H₃₆N₄O₄S 0.5H₂OCalculated: C, 60.31; H, 6.94; N, 10.42. Found: C, 60.62; H, 7.08; N,10.19. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.07 (3H, t, J=7.2 Hz),1.48 (9H, s), 1.57–1.98 (4H, m), 2.11–2.28 (1H, m), 3.92 (2H, t, J=6.2Hz), 4.02 (2H, d, J=7.4 Hz), 4.55 (2H, d, J=5.4 Hz), 4.91 (1H, bs), 5.89(1H, bs), 7.29 (1H, bs), 8.04–8.09 (1H, m), 8.24–8.25 (1H, m), 8.46–8.51(2H, m).

(2)Tert-butyl[6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]-methylcarbamate(0.32 g, 0.6 mmol) was dissolve in a solution of 4N hydrogen chloride inethyl acetate (5 ml) and the mixture was stirred at room temperature for1 h. The reaction mixture was concentrated under reduced pressure andthe residue was crystallized from ethyl acetate to give2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxamidehydrochloride (0.26 g, 92.6%) as crystals.

Melting point 274–276° C. Elemental analysis for C₂₂H₂₉N₄O₃ClS 0.5H₂OCalculated: C, 55.74; H, 6.38; N, 11.82. Found: C, 56.13; H, 6.33; N,11.86. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.1Hz), 1.56–1.75 (2H, m), 1.84–2.18 (3H, m), 3.99–4.05 (4H, m), 4.22 (2H,d, J=4.4 Hz), 8.28 (1H, d, J=1.6 Hz), 8.30 (1H, dd, J=1.6, 9.2 Hz), 8.41(1H, d, J=9.2 Hz), 8.46 (1H, s), 8.71 (3H, bs).

Example 1932-[3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carbonitrilehydrochloride

(1) A solution oftert-butyl[6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.32 g, 0.6 mmol) and cyanuric chloride (0.33 g, 1.8 mmol) inN,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[4-butoxy-6-(4-cyano-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.28 g, 93.3%) as crystals.

Melting point 160–161° C. Elemental analysis for C₂₇H₃₄N₄O₄S Calculated:C, 63.5; H, 6.71; N, 10.97. Found: C, 63.47; H, 6.69; N, 10.99.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.9 Hz), 1.08 (3H, t, J=7.5 Hz)), 1.48(9H, s), 1.60–1.72 (2H, m), 1.87–1.97 (2H, m), 2.12–2.24 (1H, m), 3.92(2H, t, J=6.4 Hz), 4.01 (2H, d, J=7.5 Hz), 4.55 (2H, d, J=5.4 Hz), 4.86(1H, bs), 8.01 (1H, dd, J=1.8, 8.2 Hz), 8.08 (1H, s), 8.29 (1H, d, J=1.8Hz), 8.49 (1H, d, J=8.2 Hz).

(2)Tert-butyl[4-butoxy-6-(4-cyano-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.20 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the residue was crystallized from ethyl acetate to give2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carbonitrilehydrochloride (0.17 g, 94.4%) as crystals.

Melting point 167–169° C. Elemental analysis for C₂₂H₂₇N₄O₂ClS H₂OCalculated: C, 56.82; H, 6.29; N, 12.05. Found: C, 56.92; H; 6.29; N,11.95. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.05 (3H, t, J=7.2Hz), 1.56–1.74 (2H, m), 1.82–2.18 (3H, m), 3.98–4.05 (4H, m), 4.22 (2H,s), 8.20 (1H, d, J=8.4 Hz), 8.30 (1H, s), 8.42 (1H, d, J=8.4 Hz) 8.70(3H, bs), 9.06 (1H, s).

Example 1943-(Aminomethyl)-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-4-phenyl-1(2H)-isoquinolinone

(1) To a suspension of3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide(4.05 g, 9 mmol) in toluene (50 ml) was added Lawesson's reagent (2.19g, 5.4 mmol), and the mixture was refluxed under heating for 1 h. Thereaction mixture was purified by silica gel column chromatography togivetert-butyl[6-(aminothiocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(3.64 g, 86.9%) as crystals.

Melting point 228–229° C. Elemental analysis for C₂₆H₃₁N₃O₃S Calculated:C, 67.07; H, 6.71; N, 9.02. Found: C, 66.88; H, 6.66; N, 8.85.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.12–2.29 (1H,m), 4.07 (2H, d, J=6.9 Hz), 4.20 (2H, d, J=5.1 Hz), 4.79 (1H, bs),7.23–7.27 (2H, m), 7.33 (1H, d, J=1.6 Hz), 7.37 (1H, bs), 7.46–7.56 (3H,m), 7.74 (1H, bs), 7.76 (1H, dd, J=1.6, 8.6 Hz.), 8.29 (1H, d, J=8.6Hz).

(2)Tert-butyl[6-(aminothiocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(3.26 g, 7 mmol) was dissolved in a solution of 4N hydrogen chloride inethyl acetate (20 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressureand the residue was suspended in tetrahydrofuran (20 ml). To theobtained mixture were added triethylamine (2.0 ml, 14 mmol) and9-fluorenylmethyl chloroformate (2.72 g, 10.5 mmol) and the mixture wasstirred with heating at 0° C. for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(3.21 g, 78.1%) as an amorphous.

¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 2.07–2.24 (1H, m), 4.08 (2H, d,J=7.4 Hz), 4.19 (1H, t, J=6.8 Hz), 4.25 (2H, d, J=2.6 Hz), 4.41 (2H, d,J=6.8 Hz), 5.35 (1H, bs), 7.21–7.60 (13H, m), 7.72–7.76 (3H, m), 8.26(1H, d, J=8.6 Hz).

(3) A suspension of9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.47 g, 0.8 mmol) and bromoacetone (0.22 g, 1.6 mmol) in ethanol (10ml) was refluxed under heating for 1 h. The reaction mixture was pouredinto water and extracted with ethyl. acetate. The extract was washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to give 9H-fluoren-9-ylmethyl[2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-4phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.41 g, 82.0%) as an amorphous.

Elemental analysis for C₃₉H₃₅N₃O₃S 0.25H₂O Calculated: C, 74.32; H,5.68; N, 6.67. Found: C, 74.36; H, 5.44; N, 6.62. ¹H-NMR(CDCl₃) δ: 1.00(6H, d, J=6.8 Hz), 2.12–2.29 (1H, m), 2.44 (3H, d, J=0.8 Hz), 4.06 (2H,d, J=7.2 Hz), 4.19 (2H, t, J=6.6 Hz), 4.27 (2H, d, J=5.0 Hz), 4.44 (2H,d, J=6.6 Hz), 4.86 (1H, bs), 6.86 (1H, q, J=0.8 Hz), 7.26–7.44 (7H, m),7.52–7.57 (5H, m), 7.75 (2H, d, J=7.0 Hz), 8.02 (1H, dd, J=1.8, 8.4 Hz),8.50 (1H, d, J=8.4 Hz).

(4) To a solution of9H-fluoren-9-ylmethyl[2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.38 g, 0.6 mmol) in N,N-dimethylformamide (10 ml) was addedpyrrolidine (0.5 ml) and the mixture was stirred at room temperature for1 h. The reaction mixture was poured into water and extracted with ethylacetate. The residue was purified by silica gel column chromatography togive3-(aminomethyl)-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-4-phenyl-1(2H)-isoquinolinone(0.13 g, 54.2%) as crystals.

Melting point 162–163° C. Elemental analysis for C₂₄H₂₄N₃OS 0.25H₂OCalculated: C, 70.64; H, 6.30; N, 10.30. Found: C, 70.96; H, 6.38; N,10.16. ¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=7.0 Hz), 1.35 (2H, bs), 2.13–2.35(1H, m), 2.45 (3H, d, J=1.2 Hz), 3.69 (2H, s), 4.23 (2H, d, J=7.2 Hz),6.85 (1H, q, J=1.2 Hz), 7.30–7.35 (2H, m), 7.43 (1H, d, J=1.4 Hz),7.48–7.59 (3H, m), 8.03 (1H, dd, J=1.4, 8.4 Hz), 8.52 (1H, d, J=8.4 Hz).

Example 195 Ethyl2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylatehydrochloride

(1) A solution of9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(Example 194(2)) (2.35 g, 4 mmol) and ethyl bromopyruvate (1.56 g, 8mmol) in ethanol (20 ml) was refluxed under heating for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give ethyl2-[3-[[[(9H-fluoren-9-ylmethoxy)carbony]amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(1.92 g, 70.3%) as crystals.

Melting point 151–152° C. Elemental analysis for C₄₁H₃₇N₃O₅S Calculated:C, 72.01; H, 5.45; N, 6.14. Found: C, 71.79; H, 5.59; N, 6.02.¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.41 (3H, t, J=7.2 Hz),2.16–2.27 (1H, m), 4.07 (2H, d, J=5.7 Hz), 4.19 (1H, t, J=6.6 Hz), 4.28(2H, d, J=5.4 Hz), 4.38–4.45 (4H, m), 4.86 (1H, bs), 7.28–7.45 (7H, m),7.75 (2H, d, J=7.1 Hz), 8.11 (1H, s), 8.13 (1H, dd, J=1.8, 8.4 Hz), 8.53(1H, d, J=8.4 Hz).

(2) To a solution of ethyl2-[3-[[[(9H-fluoren-9-ylmethoxy)carbony]amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(1.84 g, 2.7 mmol) in N,N-dimethylformamide (20 ml) was addedpyrrolidine (1 ml) and the mixture was stirred at room temperature for 1h. The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in tetrahydrofuran (20 ml) and di-t-butyl dicarbonate (0.9ml, 4 mmol) was added thereto. The obtained mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give ethyl2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(1.41 g, 93.4%) as crystals.

Melting point 170.5–171° C. Elemental analysis for C₂₉H₃₉N₃O₆SCalculated: C, 62.45; H, 7.05; N, 7.53. Found: C, 62.50; H, 7.04; N,7.53. ¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.41 (3H, t, J=7.0 Hz),1.44 (9H, s), 2.11–2.38 (1H, m), 4.19 (2H, d, J=7.2 Hz), 4.23 (2H, d,J=5.4 Hz), 4.42(2H, q, J=7.0 Hz), 4.60 (1H, bs) 7.28–7.33 (2H, m), 7.45(1H, d, J=1.8 Hz), 7.51–7.61 (3H, m), 8.11 (1H, s), 8.13 (1H, dd, J=1.8,8.4 Hz), 8.52 (1H, d, J=8.4 Hz).

(3) Ethyl2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(0.17 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized frommethanol-diisopropyl ether to give ethyl2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylatehydrochloride (0.13 g, 92.9%) as crystals.

Melting point 265–267° C. Elemental analysis for C₂₆H₂₈N₃O₃ClS 0.5H₂OCalculated: C, 61.59; H, 5.76; N, 8.29. Found: C, 61.75; H, 5.77; N,8.40. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 1.30 (3H, t, J=7.2 Hz),3.91 (2H, s), 4.11 (2H, d, J=7.2 Hz), 4.30 (2H, q, J=7.2 Hz), 7.46–7.50(3H, m), 7.60–7.72 (3H, m), 8.15 (1H, dd, J=1.4, 8.4 Hz), 8.48 (1H, d,J=8.4 Hz), 8.59 (1H, s), 8.40 (3H, bs).

Example 1962-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylicacid hydrochloride

(1) To a solution of ethyl2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate(1.12 g, 2 mmol) in tetrahydrofuran (10 ml)-ethanol (10 ml) was added 1Nsodium hydroxide (4 ml) and the mixture was stirred at room temperaturefor 2 h. The reaction mixture was poured into water, acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained crystals wererecrystallized from ethyl acetate-diisopropyl ether to give2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylicacid (1.02 g, 96.2%) as crystals.

Melting point 213–214° C. Elemental analysis for C₂₉H₃₁N₃O₅S Calculated:C, 65.27; H, 5.86; N, 7.87. Found: C, 65.01; H, 5.65; N, 7.65.¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.45 (1H, s), 2.18–2.34 (1H,m), 4.10 (2H, d, J=7.4 Hz), 4.23 (2H, d, J=5.2 Hz), 4.88 (1H, bs), 6.40(1H, bs), 7.33–7.41 (3H, m), 7.47–7.58 (3H, m), 8.03 (1H, dd, J=1.8, 8.4Hz), 8.21 (1H, s), 8.49 (1H, d, J=8.4 Hz).

(2)2-[3-[[(Tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylicacid (0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogenchloride in ethyl acetate (5 ml) and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was concentrated under reducedpressure and the residue was crystallized from ethyl acetate to give2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylicacid hydrochloride (0.13 g, 92.9%) as crystals.

Melting point 281–283° C. Elemental analysis for C₂₄H₂₄N₃O₃ClS H₂OCalculated: C, 59.07; H, 5.37; N, 8.61. Found: C, 59.32; H, 5.42; N,8.57. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.01–2.21 (1H, m), 3.90(2H, s), 4.10 (2H, d, J=7.8 Hz), 7.45–7.51 (3H, m), 7.56–7.64 (3H, m),8.41 (1H, dd, J=1.7, 8.4 Hz), 8.48 (1H, d, J=8.4 Hz) 8.53 (1H, s), 8.57(3H, bs).

Example 1972-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxamidehydrochloride

(1) A solution of2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylicacid (0.80 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt(0.46 g, 3 mmol) in N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to givetert-butyl[6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.75 g, 93.8%) as crystals.

Melting point 248–249° C. Elemental analysis for C₂₉H₃₂N₄O₄S 0.25H₂OCalculated: C, 64.84; H, 6.10; N, 10.43. Found: C, 64.98; H, 6.21; N,10.23. ¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=6.8 Hz), 1.44 (9H, s), 2.19–2.34(1H, m), 4.10 (2H, d, J=7.4 Hz), 4.24 (2H, d, J=5.4 Hz), 4.65 (1H, bs),5.84 (1H, bs), 7.29–7.34 (2H, m), 7.44 (1H, d, J=1.8 Hz), 7.51–7.61 (3H,m), 8.00 (1H, dd, J=1.8, 8.4 Hz), 8.11 (1H, s), 8.52 (1H, d, J=8.4 Hz).

(2)Tert-butyl[6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]-methylcarbamate(0.32 g, 0.6 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressureand the residue was crystallized from ethyl acetate to give2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxamidehydrochloride (0.27 g, 96.4%) as crystals.

Melting point 235–237° C. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz),2.05–2.21 (1H, m), 3.92 (2H, s), 4.10 (2H, d, J=7.8 Hz), 7.39 (1H, d,J=1.6 Hz), 7.45–7.50 (2H, m), 7.60–7.66 (3H, m), 7.70 (1H, bs), 7.79(1H, bs), 8.28 (1H, d, J=1.6, 8.4 Hz), 8.30 (1H, s), 8.47 (1H, d, J=8.4Hz), 8.58 (3H, bs).

Example 1982-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carbonitrilehydrochloride

(1) A solution oftert-butyl[6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.32 g, 0.6 mmol) and cyanuric chloride (0.33 g, 1.8 mmol) inN,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[6-(4-cyano-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.28 g, 90.3%) as crystals.

Melting point 209–211° C. Elemental analysis for C₂₉H₃₀N₄O₃S Calculated:C, 67.68; H, 5.88; N, 10.89. Found: C, 67.72; H, 5.92; N, 10.62.¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=6.8 Hz), 1.44 (9H, s), 2.19–2.38 (1H,m), 4.10 (2H, d, J=7.8 Hz), 4.24 (2H, d, J=5.6 Hz), 4.58 (1H, bs),7.28–7.32 (2H, m), 7.49 (1H, d, J=1.4 Hz), 7.52–7.63 (3H, m), 7.95 (1H,s), 7.96 (1H, dd, J=1.4, 8.4 Hz), 8.54 (1H, d, J=8.4 Hz).

(2)Tert-butyl[6-(4-cyano-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.21 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressureand the residue was crystallized from ethyl acetate to give2-[3-aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carbonitrilehydrochloride (0.17 g, 94.4%) as crystals.

Melting point 274–276° C. Elemental analysis for C₂₄H₂₃N₄OClS 0.5H₂OCalculated: C, 62.67; H, 5.26; N, 12.18. Found: C, 62.57; H, 5.06; N,12.08. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.01–2.21 (1H, m),3.89 (2H, m), 4.11 (2H, d, J=7.2 Hz), 7.45–7.51 (3H, m), 7.61–7.64 (3H,m), 8.14 (1H, dd, J=1.8, 8.4 Hz), 8.48 (1H, d, J=8.4 Hz), 8.62 (3H, bs),8.95 (1H, s).

Example 1993-(Aminomethyl)-4-butoxy-2-isobutyl-6-(1H-pyrrol-1-yl)-1(2H)-isoquinolinonedihydrochloride

(1) A solution oftert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.41 g, 1 mmol) and 2,5-dimethoxytetrahydrofuran (0.19 ml, 1.5 mmol) inacetic acid (10 ml) was stirred at 80° C. for 2 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to givetert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-pyrrol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.31 g, 67.4%) as crystals.

Melting point 164–166° C. Elemental analysis for C₂₇H₃₇N₃O₄ Calculated:C, 69.35; H, 7.98; N, 8.99. Found: C, 69.29; H, 8.28; N, 8.87.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.4 Hz), 1.47(9H, s), 1.51–1.69 (2H, m), 1.81–1.95 (2H, m), 2.04–2.25 (1H, m), 3.89(2H, t, J=6.5 Hz), 3.99 (2H, d, J=7.8 Hz), 4.53 (2H, d, J=5.6 Hz), 4.80(1H, bs), 6.41–6.43 (2H, m), 7.21–7.23 (2H, m), 7.50–7.56 (1H, m), 7.62(1H, d, J=1.8 Hz), 8.43–8.48 (1H, m).

(2)Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-pyrrol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.23 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressureand the obtained crystals were recrystallized from methanol-diethylether to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1H-pyrrol-1-yl)-1(2H)-isoquinolinonedihydrochloride (0.19 g, 95.0%) as crystals.

Melting point 156–157° C. Elemental analysis for C₂₂H₃₀N₃O₂Cl 0.5H₂OCalculated: C, 63.99; H, 7.57; N, 10.18. Found: C, 64.23; H, 7.86; N,10.25. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.00 (3H, t, J=7.3Hz), 1.55–1.66 (2H, m), 1.81–2.13 (3H, m), 3.96–4.03 (4H, m), 4.19 (2H,bs), 6.39 (2H, t, J=2.2 Hz), 7.55 (2H, t, J=2.2 Hz), 7.70 (1H, d, J=2.0Hz), 7.89 (1H, dd, J=2.0, 8.8 Hz), 8.33 (1H, d, J=8.8 Hz), 8.72 (3H,bs).

Example 2003-(Aminomethyl)-4-butoxy-2-isobutyl-6-(1H-tetrazol-1-yl)-1(2H)-isoquinolinonehydrochloride

(1) To a solution oftert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.41 g, 1 mmol) in acetic acid (5 ml) was added trimethyl orthoformate(0.33 ml, 3 mmol) and the mixture was stirred at room temperature for 30min. To the obtained mixture was added sodium azide (0.10 g, 1.5 mmol)and the mixture was stirred at 80° C. for 2 h. The reaction mixture waspoured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to givetert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-tetrazol-1-yl)-1,2-dihydro-3-isoquinolinyl]-methylcarbamate(0.31 g, 66.0%) as crystals.

Melting point 199–200° C. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.05(3H, t, J=7.3 Hz), 1.48 (9H, s), 1.54–1.69 (2H, m), 1.83–1.97 (2H, m),2.12–2.26 (1H, m), 3.91 (2H, t, J=6.4 Hz), 4.03 (2H, d, J=7.4 Hz), 4.56(2H, d, J=5.4 Hz), 4.80 (1H, bs), 7.78 (1H, dd, J=2.2, 8.8 Hz), 8.09(1H, d, J=2.2 Hz), 8.62 (1H, d, J=8.8 Hz), 9.15 (1H, s).

(2)Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-tetrazol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.24 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressureand the obtained crystals was crystallized from methanol-diethyl etherto give3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1H-tetrazol-1-yl)-1(2H)-isoquinolinonehydrochloride (0.19 g, 95.0%) as crystals.

Melting point 177–179° C. Elemental analysis for C₁₉H₂₇N₆O₂Cl 0.5H₂OCalculated: C, 54.87; H, 6.79; N, 20.21. Found: C, 55.08; H, 7.19; N,20.00. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.01 (3H, t, J=7.3Hz), 1.43–1.67 (2H, m), 1.82–2.10 (3H, m), 3.98–4.04 (4H, m), 4.23 (2H,bs), 8.17 (1H, dd, J=2.0, 8.6 Hz), 8.23 (1H, d, J=2.0 Hz), 8.52 (1H, d,J=8.6 Hz), 8.73 (3H, bs), 10.38 (1H, s).

Example 2013-(Aminomethyl)-4-butoxy-2-isobutyl-6-(1H-1,2,3-triazol-1-yl)-1(2H)-isoquinolinonehydrochloride

(1) To a solution oftert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.41 g, 1 mmol) in methanol (10 ml) was addedN′-(2,2-dichloroethylidene)-4-methylbenzenesulfonohydtazide (0.28 g, 1mmol) and the mixture was stirred at 0° C. for 1 h and at roomtemperature for 12 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto givetert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.21 g, 45.7%) as crystals.

Melting point 190–191° C. Elemental analysis for C₂₅H₃₅N₅O₄ Calculated:C, 63.97; H, 7.51; N, 14.91. Found: C, 64.95; H, 7.69; N, 14.63.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.0 Hz), 1.48(9H, s), 1.54–1.69 (2H, m), 1.83–1.97 (2H, m), 2.04–2.24 (1H, m), 3.92(2H, t, J=6.6 Hz), 4.02 (2H, d, J=7.8 Hz), 4.55 (2H, d, J=5.6 Hz), 4.82(1H, bs), 7.81 (1H, dd, J=2.2, 8.8 Hz), 7.91 (1H, d, J=1.3 Hz), 8.12(1H, d, J=1.3 Hz), 8.13 (1H, d, J=2.2 Hz), 8.56 (1H, d, J=8.8 Hz).

(2)tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.14 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml,) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure togive3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1H-1,2,3-triazol-1-yl)-1(2H)-isoquinolinonehydrochloride (81 mg, 62.3%) as an amorphous.

¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.01 (3H, t, J=7.3 Hz),1.49–1.68 (2H, m), 1.82–2.12 (3H, m), 3.89–4.03 (4H, m), 4.22 (2H, d,J=4.4 Hz), 8.09 (1H, d, J=1.3 Hz), 8.18 (1H, dd, J=2.0, 8.6 Hz), 8.24(1H, d, J=2.0 Hz), 8.48 (1H, d, J=8.6 Hz), 8.75 (3H, bs), 9.11 (1H, d,J=1.3 Hz).

Example 2023-(Aminomethyl)-4-butoxy-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1(2H)-isoquinolinonehydrochloride

(1) A solution oftert-butyl(4-butoxy-6-cyano-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.85 g, 2 mmol), sodium carbonate (0.85 g, 8 mmol) and hydroxylaminehydrochloride (0.42 g, 6 mmol) in ethanol (20 ml) was refluxed withstirring for 12 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto givetert-butyl[6-[amino(hydroxyimino)methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.81 g, 88.0%) as crystals.

Melting point 209–210° C. Elemental analysis for C₂₄H₃₆N₄O₅ Calculated:C, 62.59; H, 7.88; N, 12.16. Found: C, 62.49; H, 7.93; N, 11.98.¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.3 Hz),1.49–1.66 (11H, m), 1.78–1.91 (2H, m), 2.09–2.24 (1H, m), 3.68–3.84 (2H,m), 3.98 (2H, t, J=6.6 Hz), 4.51 (2H d, J=4.8 Hz), 5.02 (2H, s), 5.16(1H, bs), 5.37 (1H, bs), 7.62 (1H, d, J=8.3 Hz), 7.82 (1H, s), 8.25 (1H,d, J=8.3 Hz).

(2) To a solution oftert-butyl[6-[amino(hydroxyimino)methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.78 g, 1.7 mmol) in ethyl acetate (10 ml) tetrahydrofuran (10 ml) wasadded 1,1′-carbonyldiimidazole (0.83 g, 5.1 mmol) and the mixture wasstirred at 80° C. for 2 h. The reaction mixture was poured into waterand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-diisopropylether to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.54 g, 65.9%) as crystals.

Melting point 223–224° C. Elemental analysis for C₂₅H₃₄N₄O₆ 0.25H₂OCalculated: C, 61.15; H, 7.08; N, 11.41 Found: C, 61.00; H, 7.11; N,11.13. ¹H-NMR(CDCl₃) δ: 0.86 (6H, d, J=6.6 Hz), 0.98 (3H, t, J=7.3 Hz),1.42 (9H, s), 1.43–1.61 (2H, m), 1.76–1.90 (2H, m), 2.04–2.15 (1H, m),3.86–3.92 (4H, m), 4.39 (2H, d, J=4.4 Hz), 7.36 (1H, bs), 7.94 (1H, dd,J=1.4, 8.4 Hz), 8.15 (1H, d, J=1.4 Hz), 8.38 (1H, d, J=8.4 Hz).

(3)Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.44 g, 0.9 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (10 ml) and the mixture was stirred at room temperaturefor 3 h. The reaction mixture was concentrated under reduced pressureand the obtained crystals were recrystallized from methanol-diethylether to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1(2H)-isoquinolinonehydrochloride (0.36 g, 94.7%) as crystals.

Melting point 256–258° C. Elemental analysis for C₂₀H₂₇N₄O₄Cl 0.25H₂OCalculated: C, 56.20; H, 6.49; N, 13.11. Found: C, 56.23; H, 6.65; N,12.98. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.4 Hz), 1.01 (3H, t, J=7.3Hz), 1.46–1.64 (2H, m), 1.83–2.16 (3H, m), 3.95–4.02 (4H, m), 4.21 (2H,s), 8.03 (1H, dd, J=1.8, 8.4 Hz), 8.21 (1H, d, J=1.8 Hz), 8.43 (1H, d,J=8.4 Hz), 8.68 (3H, bs).

Example 2033-(Aminomethyl)-4-butoxy-2-isobutyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1(2H)-isoquinolinonehydrochloride

(1) A solution oftert-butyl[6-[amino(hydroxyimino)methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.46 g, 1 mmol), acetic anhydride (0.14 ml, 1.5 mmol) and a catalyticamount of acetic acid in tetrahydrofuran (10 ml) was refluxed underheating for 10 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was crystallized from ethyl acetate-diisopropylether to givetert-butyl[4-butoxy-2-isobutyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.22 g, 45.8%) as crystals.

Melting point 151.5–152° C. Elemental analysis for C₂₆H₃₆N₄O₆Calculated: C, 64.44; H, 7.49; N, 11.56. Found: C, 64.12; H, 7.74; N,11.54. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.05 (3H, t, J=7.3 Hz),1.47 (9H, s), 1.56–1.68 (2H, m), 1.86–1.95 (2H, m), 2.15–2.24 (1H, m),2.70 (3H, s), 3.92 (2H, t, J=6.6 Hz), 4.02 (2H, d, J=7.5 Hz), 4.54 (2H,d, J=5.7 Hz), 4.78 (1H, bs), 8.15 (1H, dd, J=1.8, 8.7 Hz), 8.42 (1H, d,J=1.8 Hz), 8.51 (1H, d, J=8.7 Hz).

(2)Tert-butyl[4-butoxy-2-isobutyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]-methylcarbamate(0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 3 h. The reaction mixture was concentrated under reduced pressureand the obtained crystals were recrystallized from methanol-diethylether to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1(2H)-isoquinolinonehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 230–232° C. Elemental analysis for C₂₁H₂₉N₄O₃Cl 0.25H₂OCalculated: C, 59.29; H, 6.99; N, 13.17. Found: C, 59.50; H, 7.02; N,12.95. ¹ H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.03 (3H, t, J=7.3Hz), 1.52–1.67 (2H, m), 1.70–1.99 (2H, m), 2.02–2.12 (1H, m), 2.73 (3H,s), 3.95–4.02 (4H, m), 4.22 (2H, s), 8.18 (1H, d, J=8.4 Hz), 8.39 (1H,s), 8.45 (1H, d, J=8.4 Hz), 8.67 (3H, bs).

Example 2043-(Aminomethyl)-4-butoxy-2-isobutyl-6-(1H-tetrazol-5-yl)-1(2H)-isoquinolinonehydrochloride

(1) A solution oftert-butyl(4-butoxy-6-cyano-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.85 g, 2 mmol), triethylamine hydrochloride (0.34 g, 2.5 mmol) andsodium azide (0.16 g, 2.5 mmol) in toluene (20 ml) was stirred at 90° C.for 24 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedcrystals were recrystallized from tetrahydrofuran-diisopropyl ether togive tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.50 g, 53.2%) as crystals.

Melting point 152–153° C. Elemental analysis for C₂₄H₃₄N₆O₄ 0.25H₂OCalculated: C, 60.68; H, 7.32; N, 17.69. Found: C, 60.98; H, 7.20; N,17.29. ¹H-NMR(CDCl₃) δ: 0.95–1.02 (9H, m), 1.48–1.61 (11H, m), 1.81–1.92(2H, m), 2.14–2.27 (1H, m), 3.91 (2H, t, J=6.6 Hz), 4.08 (2H, d, J=7.2Hz), 4.57 (2H, d, J=5.2 Hz), 4.79 (1H, bs), 5.39 (1H, bs), 8.12 (1H, dd,J=1.5, 8.5 Hz), 8.40 (1H, d, J=8.5 Hz), 8.46 (1H, d, J=1.5 Hz).

(2)Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.47 g, 1 mmol) was dissolved in a solution of 4N hydrogen chloride inethyl acetate (5 ml) and the mixture was stirred at room temperature for1 h. The reaction was concentrated under reduced pressure and theobtained crystals crystallized from methanol-diethyl ether to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1H-tetrazol-5-yl)-1(2H)-isoquinolinonehydrochloride (0.38 g, 92.7%) as crystals.

Melting point 252–254° C. Elemental analysis for C₁₉H₂₇N₆O₂Cl 0.25H₂OCalculated: C, 55.47; H, 6.74; N, 20.43. Found: C, 55.63; H, 6.67; N,20.21. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=7.0 Hz), 1.02 (3H, t, J=7.3Hz), 1.50–1.69 (2H, m), 1.85–2.10 (3H, m), 3.98–4.02 (4H, m), 4.22 (2H,s), 8.30 (1H, dd, J=1.4, 8.4 Hz), 8.48 (1H, d, J=8.4 Hz), 8.51 (1H, d,J=1.4 Hz), 8.63 (3H, bs).

Example 2052-(Aminomethyl)-4-isobutyl-5-phenyl[1,7]naphthyridin-8(7H)-onedihydrochloride

(1) To a suspension of 3-benzoylpyridin-2-carboxylic acid (2.27 g, 10mmol) in toluene (20 ml) was added thionyl chloride (0.88 ml, 12 mmol)and the mixture was stirred at 100° C. for 2 h. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved intetrahydrofuran (20 ml). The obtained solution was added dropwise to(isobutylamino)-acetonitrile (1.68 g, 15 mmol) in N,N-dimethylacetamide(20 ml) and the mixture was stirred at 70° C. for 12 h. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. To a solution of the residueand acetic anhydride (1.1 ml, 12 mmol) in acetonitrile (6.0 ml, 40 mmol)at 0° C. and the mixture was stirred at room temperature for 15 h. Waterwas added to the reaction mixture and the mixture was stirred at roomtemperature for 30 min. The precipitated crystals were collected byfiltration. The obtained crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to give7-isobutyl-8-oxo-5-phenyl-7,8-dihydro[1,7]naphthyridine-6-carbonitrile(2.65 g, 87.5%) as crystals.

Melting point 221–222° C. Elemental analysis for C₁₉H₁₇N₃O Calculated:C, 75.23; H, 5.65; N, 13.85. Found: C, 75.20; H, 5.72; N, 13.85.¹H-NMR(CDCl₃) δ: 1.06 (6H, d, J=7.0 Hz), 2.30–2.51 (1H, m), 4.24 (2H, d,J=7.8 Hz), 7.37–7.46 (2H, m), 7.52–7.61 (4H, m), 7.72 (1H, dd, J=1.8,8.3 Hz), 9.01 (1H, dd, J=1.8, 8.4 Hz).

(2) A suspension of7-isobutyl-8-oxo-5-phenyl-7,8-dihydro[1,7]naphthyridine-6-carbonitrile(2.43 g, 8 mmol), Raney-cobalt (2.4 ml) and 25% aqueous ammonia (3.2 ml)in tetrahydrofuran (100 ml) was stirred under a hydrogen atmosphere at 5atm and 60° C. for 3 h. Raney-cobalt was filtered off and the filtratewas concentrated under reduced pressure. The residue was dissolved intetrahydrofuran (30 ml) and to the obtained solution was addeddi-t-butyl dicarbonate (2.3 ml, 10 mmol). The mixture was stirred atroom temperature for 1 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto givetert-butyl(7-isobutyl-8-oxo-5-phenyl-7,8-dihydro[1,7]naphthyridin-6-yl)methylcarbamate(0.21 g, 6.4%) as crystals.

Melting point 176–177° C. Elemental analysis for C₂₄H₂₉N₃O₃ Calculated:C, 70.74; H, 7.17; N, 10.31. Found: 70.59; H, 7.18; N, 10.26.¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.23–2.32 (1H,m), 4.14 (2H, d, J=7.2 Hz), 4.22 (2H, d, J=5.4 Hz), 4.93 (1H, bs),7.26–7.33 (4H, m), 7.45–7.57 (3H, m), 8.76–8.77 (1H, m).

(3)Tert-butyl(7-isobutyl-8-oxo-5-phenyl-7,8-dihydro[1,7]naphthyridin-6-yl)methylcarbamate(0.16 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml) and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressureand the obtained crystals were recrystallized from methanol-ethylacetate to give2-(aminomethyl)-4-isobutyl-5-phenyl[1,7]naphthyridin-8(7H)-onedihydrochloride (0.12 g, 80.0%) as crystals.

Melting point 293° C. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz),2.06–2.19 (1H, m), 3.91 (2H, d, J=3.9 Hz), 4.14 (2H, d, J=7.2 Hz),7.41–7.44 (3H, m), 7.50–7.62 (3H, m), 7.71–7.76 (1H, m), 8.79 (3H, bs),8.88–8.90 (1H, m).

Example 2063-(Aminomethyl)-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) To a mixture oftert-butyl(6-cyano-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isquinolinyl)methylcarbamate(0.86 g, 2.0 mmol), hydroxylamine hydrochloride (0.21 g, 3.0 mmol) andethanol (20 ml) was added potassium t-butoxide (0.34 g, 3.0 mmol) atroom temperature and the mixture was stirred at 75–80° C. for 3 h. Thereaction mixture was poured into water (100 ml) and the mixture wasextracted with ethyl acetate (50 ml). The organic layer was washed withsaturated brine (20 ml) and dried over anhydrous magnesium sulfate (6g). The solvent was evaporated and the residue was purified by silicagel column chromatography (n-hexane-ethyl acetate=1:1 (v/v)) to givetert-butyl{6-[amino(hydroxyimino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl}methylcarbamate(0.57 g, 62%) as a colorless powder.

¹H-NMR(CDCl₃) δ: 0.90 (6H, d, J=6.6 Hz), 1.38 (9H, s), 2.05–2.20 (1H,m), 3.85–4.00 (4H, s), 5.84 (2H, bs), 7.29 (1H, d, J=1.8 Hz), 7.31 (1H,br), 7.35–7.55 (5H, m), 7.55 (1H, dd, J=1.8, 8.4 Hz), 9.83 (1H, s).

(2)Tert-butyl{6-[amino(hydroxyimino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl}methylcarbamate(0.25 g, 0.54 mmol) was dissolved in ethyl acetate (10 ml) andN,N′-carbonyldiimidazole (0.26 g, 1.6 mmol) was added. The mixture wasrefluxed under heating for 3 h. To the reaction mixture were added 0.1 Maqueous citric acid solution (25 ml) and ethyl acetate (50 ml). Theorganic layer was washed with 0.1 M aqueous citric acid solution (25ml), and then saturated brine (25 ml), dried over anhydrous magnesiumsulfate (12 g) and concentrated under reduced pressure. The residue wasrecrystallized from diisopropyl ether-ethyl acetate=2:1 (v/v) to givetert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.24 g, 93%) as a colorless powder.

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.15–2.35 (1H,m), 4.10 (2H, d, J=7.2 Hz), 4.22 (2H, d, J=5.4 Hz), 4.64 (1H, br),7.25–7.35 (3H, m), 7.45–7.60 (3H, m), 7.82 (1H, dd, J=1.7, 8.4 Hz), 8.52(1H, d, J=8.4 Hz).

(3)Tert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.18 g, 0.37 mmol) was dissolved in ethanol (4 ml) and a solution (4ml) of 4N hydrogen chloride in ethyl acetate was added. The mixture wasstirred at room temperature for 30 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was washed withdiisopropyl ether (2 ml) and recrystallized from ethyl acetate-ethanol(20:1) to give3-(aminomethyl)-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1(2H)-isoquinolinonehydrochloride (0.12 g, 80%) as a colorless powder.

Elemental analysis for C₂₂H₂₂N₄O₃ HCl 0.5H₂O, Calculated: C, 60.62; H,5.55; N, 12.85. Found: C, 61.01; H, 5.49; N, 12.21. ¹H-NMR(DMSO-d₆) δ:0.93 (6H, d, J=6.6 Hz), 2.00–2.25 (1H, m), 3.88 (2H, s), 4.08 (2H, d,J=7.2 Hz), 7.35–7.45 (3H, m), 7.55–7.65 (3H, m), 7.96 (1H, dd, J=1.8,8.4 Hz), 8.46 (3H, br), 8.50 (1H, d, J=8.4 Hz).

Melting point 253° C. (decomposition)

Example 2073-(Aminomethyl)-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1) A mixture oftert-butyl{6-[amino(hydroxyimino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl}methylcarbamate(0.50 g, 1.1 mmol), acetic acid (5 ml) and acetic anhydride (0.12 ml,1.3 mmol) was stirred at room temperature for 20 min. To the reactionmixture was added 10% palladium-activated carbon (0.05 g) under anitrogen atmosphere and the mixture was stirred at room temperature and1 atm under a hydrogen atmosphere for 12 h. The insoluble material wasfiltered off and the solvent was evaporated. Diisopropyl ether (2 ml)was added to the residue to givetert-butyl{6-[amino(imino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl}methylcarbamatediacetate (0.92 g, 85%) as a brown powder.

¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.38 (9H, s), 1.80 (6H, s),2.05–2.25 (1H, m), 3.90–4.05 (4H, m), 7.23 (1H, d, J=1.4 Hz), 7.30–7.45(3H, m), 7.45–7.60 (3H, m), 7.76 (1H, dd, J=1.4, 8.2 Hz), 8.44 (1H, d,J=8.2 Hz), 10.59 (2H, br).

(2) Chlorocarbonylsulfenyl chloride (0.04 ml, 0.45 mmol) was added to amixture oftert-butyl{6-[amino(imino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl}methylcarbamatediacetate (0.25 g, 0.43 mmol), sodium carbonate (0.40 g, 3.8 mmol),water (5 ml) and tetrahydrofuran (5 ml) while stirring vigorously underice-cooling. The reaction mixture was stirred for 3 h, warmed to roomtemperature and stirred for 1 h more. The reaction mixture was added to1N hydrochloric acid (30 ml) and extracted twice with ethyl acetate (30ml). The organic layers were combined and washed with 1N hydrochloricacid (10 ml) and then saturated brine (10 ml), dried over anhydrousmagnesium sulfate (12 g) and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (n-hexane-ethylacetate=1:1 (v/v)) to givetert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isioquinolinyl]methylcarbamate(0.084 g, 39%) as a yellow powder.

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.15–2.35 (1H,m,), 4.03 (2H, d, J=6.6 Hz), 4.19 (2H, d, J=5.2 Hz), 4.73 (1H, br),7.25–7.35 (3H, m), 7.50–7.60 (3H, m), 7.97 (1H, dd, J=1.8, 8.4 Hz), 8.53(1H, d, J=8.4 Hz), 11.44 (1H, bs).

(3)Tert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.050 g, 0.10 mmol) was dissolved in tetrahydrofuran (3 ml) and asolution (2 ml) of 4N hydrogen chloride in ethyl acetate was added. Themixture was stirred at room temperature for 24 h. The reaction mixturewas concentrated under reduced pressure and diisopropyl ether-ethylacetate (2:1) was added to the residue to give3-(aminomethyl)-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)-4-phenyl-1(2H)-isoquinolinonehydrochloride (0.041 g, 94%) as a pale-yellow powder.

Elemental analysis for C₂₂H₂₂N₄O₂S HCl 0.75H₂O, Calculated: C, 57.89; H,5.41; N, 12.27. Found: C, 57.95; H, 5.41; N, 11.58. ¹H-NMR(DMSO-d₆) δ:0.95 (6H, d J=6.6 Hz) 2.00–2.20 (1H, m), 3.93(2H, s), 4.09 (2H, d, J=7.4Hz), 7.35–7.50 (2H, m), 7.50–7.65 (3H, m), 7.86 (1H, d, J=1.8 Hz) 8.32(1H, dd, J=1.8, 8.2 Hz), 8.48 (1H, d, J=8.2 Hz), 8.50 (3H, bs).

Melting point 232–237° C.

Example 2086-Bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile

To a mixture of 2-benzoyl-4-bromobenzoic acid (5.0 g), toluene (65 ml)and dimethylformamide (0.1 ml) was added dropwise thionyl chloride (1.42ml) under a nitrogen atmosphere, and the mixture was stirred at 50° C.for 1.5 h. The solvent was evaporated and toluene (10 ml) was added tothe residue. The mixture was heated to around 90° C.Diisopropylethylamine (4.21 ml) was added to the obtained solution andthe mixture was stirred for about 5 min. Isobutylaminoacetonitrile (2.75g) was added and the mixture was stirred at around the same temperaturefor 3 h. The reaction mixture was cooled to 25° C. and 1N hydrochloricacid (50 ml) was added and stirred. The organic layer was separated andwashed with 10% brine (50 ml). The solvent was evaporated to give2-benzoyl-4-bromo-(N-cyanomethyl)-N-(isobutyl)benzamide. Acetonitrile(15 ml) and ethanol (15 ml) were added to the residue, and aceticanhydride (1.85 ml) and 1,8-diazabicyclo[5,4,0]-7-undecene (4.90 ml)were successively added dropwise to the mixture below 40° C. Thereaction mixture was heated to 50° C. and the mixture was stirred for 1h. The reaction mixture was cooled to around 25° C. and water (12.5 ml)was added dropwise. The mixture was stirred at the same temperature for1 h. The precipitated crystals were collected by filtration and washedwith 70% ethanol to give the title compound (5.31 g, yield 85%).

¹H-NMR(300 MHz, CDCl₃) δ: 1.04 (6H, d, J=6.7 Hz), 2.30–2.39(1H, m),4.15(2H, d, J=7.5 Hz), 7.39–7.44(3H, m), 7.55–7.60(3H, m), 7.76(1H, dd,J=1.9 Hz, 8.6 Hz), 8.39(1H, d, J=8.6 Hz)

Example 209(3-(Aminomethyl)-6-bromo-2-isobutyl-4-phenylisoquinolin-1(2H)-one

A mixture of6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile(16.0 g), sponge cobalt (manufactured by Kawaken Fine Chemicals Co.,Ltd.; trademark: ODHT-60) (4 ml), 25% ammonium hydroxide (2 ml) andtetrahydrofuran. (80 ml) was stirred at 60° C. at a 1 MPa hydrogenpressure for 4 h and the catalyst was filtered off. The solvent wasevaporated and acetonitrile (48 ml) was added to the residue. Themixture was heated to about 70° C. The obtained solution was cooled to25° C. to give crystals, and water (80 ml) was added dropwise. Theobtained mixture was cooled to around 5° C. and the mixture was stirredfor 1 h. The precipitated crystals were collected by filtration to givethe title compound (14.8 g, yield 91.4%).

¹H-NMR(CDCl₃) δ: 1.00(6H, d, J=6.7 Hz), 1.10(2H, br), 2.25(1H, m),3.65(2H, s), 4.20(2H, d, J=7.4 Hz), 7.07(1H, d, J=1.9 Hz), 7.08–7.28(2H,m), 7.45–7.54(4H, m), 8.32(1H, d, J=8.6 Hz)

Example 2103-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile

A mixture of3-(aminomethyl)-6-bromo-2-isobutyl-4-phenylisoquinolin-1(2H)-one (15.0g), zinc cyanide (2.74 g), tetrakis(triphenylphosphine)palladium (1.35g), N-methylpyrrolidone (75 ml) and water (0.75 ml), was stirred under anitrogen atmosphere at an inner temperature of 54–56° C. To the reactionmixture was added dropwise saturated aqueous ammonium chloride-25%ammonium hydroxide-water (4:1:4, 37.5 ml) over 30 min at the sametemperature, and the mixture was stirred for 1 h and below 5° C. for 1h. The obtained crystals were collected by filtration and suspended inacetonitrile (105 ml). The suspension was dissolved at 80° C. To theobtained solution was added activated carbon (0.75 g) and the mixturewas stirred for 10 min. The activated carbon was filtered off and washedwith acetonitrile (15 ml). The filtrate was combined and cooled to 25°C. to give crystals. Water (120 ml) was added dropwise and the obtainedmixture was cooled to 5° C. and stirred for 1 h. The obtained crystalswere collected by filtration to give the title compound (9.6 g, yield74.5%).

¹H-NMR(300 MHz, CDCl₃) δ: 1.01(6H, d, J=6.8 Hz), 1.13(2H, br),2.22–2.31(1H, m), 3.69(2H, s), 4.23(2H, d, J=7.5 Hz), 5.55–5.95(2H, br),7.24–7.28(3H, m), 7.50–7.56(3H, m), 7.61(1H, dd, J=1.5 Hz, 8.3 Hz),8.55(1H, d, J=8.3 Hz)

Example 2113-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carboxamide½ dimethyl sulfoxide solvate

A mixture of3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile(20.0 g), 2N aqueous sodium-hydroxide solution (6 ml), dimethylsulfoxide (100 ml) and water (40 ml) was stirred at an inner temperatureof 85° C. for 30 min. The reaction mixture was cooled to 40° C., cooledto not higher than 5° C. and stirred for 1 h. The precipitated crystalswere collected by filtration and washed twice with water (40 ml) to givethe title compound (21.7 g) as pale yellow crystals.

¹H-NMR(300 MHz, CDCl₃) δ: 1.01(6H, d, J=6.7 Hz), 2.20–2.32(1H, m),2.62(6H, s; DMSO), 3.68(2H, s), 4.24(2H, d, J=7.4 Hz), 5.55–5.95(2H,br), 7.25–7.30(2H, m), 7.39(1H, d, J=1.6 Hz), 7.45–7.55(3H, m), 7.79(1H,dd, J=1.5 Hz, 8.3 Hz), 8.54(1H, d, J=8.3 Hz)

Example 2123-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carboxamide

A mixture of3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carboxamide(10 g), methanol (40 ml) and 1N hydrochloric acid (20 ml) was heated to60° C. 1N Hydrochloric acid (ca. 7 ml) was added to the reaction mixtureat around the same temperature to adjust pH to 2.0, and activated,carbon (0.5 g) was added. The mixture was stirred for about 10 min andactivated carbon was filtered off. The obtained solution was washed withmethanol-water (2:1) (10 ml) and heated again to around 60° withstirring. 5% Ammonium hydroxide was added to the reaction mixture whilekeeping the same temperature to adjust pH to 7.3, and water (10 ml) wasadded dropwise. The obtained mixture was cooled to 25° C., ice-cooledand stirred at around 5° C. for 1 h. The precipitated crystals (8.48 g)were collected by filtration, suspended in ethyl acetate (85 ml) andstirred at around 75° C. for 2 h. The obtained mixture was allowed tocool for 1 h, ice-cooled and stirred at around 5° C. for 1 h. Theprecipitated crystals were collected by filtration and washed withpreviously-cooled ethyl acetate (17 ml) to give the title compound ascrystals (8.02 g).

Powder X-ray crystal diffraction data Diffraction angle: 2θ(°)(angstrom) spacing: d value 8.96 9.86 13.7 6.46 15.9 5.56 16.6 5.34 22.83.89 24.4 3.65 24.7 3.60 25.3 3.52 25.7 3.46

Example 213 7-(Aminomethyl)-6-isobutyl-8-phenyl[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one

This compound was synthesized according to the method similar to that inExample 106.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.32 (2H, br), 2.26 (1H, m),3.64 (2H, s), 4.19 (2H, d, J=7.6 Hz), 6.00 (2H, s), 6.29 (1H, s),7.23–7.28 (2H, m), 7.40–7.54 (3H, m), 7.83 (1H, s).

Example 214 Ethyl2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylatehydrochloride

(1) A solution of9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(1.76 g, 3 mmol) and ethyl 2-choloroacetate (0.99 g, 6 mmol) in ethanol(20 ml) was refluxed under heating for 12 h. The reaction mixture waspoured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give ethyl2-[3-({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3thiazole-5-carboxylate(1.46 g, 69.9%) as crystals.

Melting point 157–158° C. Elemental analysis for C₄₂H₃₉N₃O₅S Calculated:C, 72.29; H, 5.63; N, 6.02. Found: C, 72.12; H, 5.69; N, 5.79.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.9 Hz), 1.37 (3H, t, J=7.2 Hz),2.12–2.29 (1H, m), 2.69 (3H, s), 4.08 (2H, d, J=6.0 Hz), 4.21 (1H, t,J=6.9 Hz), 4.26 (2H, d, J=4.8 Hz), 4.33 (2H, q, J=7.2 Hz), 4.44 (2H, d,J=6.9 Hz), 5.23 (1H, bs), 7.26–7.45 (7H, m), 7.51–7.60 (5H, m), 7.75(2H, d, J=7.5 Hz), 7.97 (1H, d, J=8.4 Hz), 8.46 (1H, d, J=8.4 Hz).

(2) To a solution of ethyl2-[3-({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylate(1.40 g, 2 mmol) in N,N-dimethylformamide (20 ml) was added pyridine (1ml). The mixture was stirred at room temperature for 1 h. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was dissolved intetrahydrofuran (20 ml), and di-t-butyl dicarbonate (0.69 ml, 3 mmol)was added thereto. The resulting mixture was stirred at room temperaturefor 1 h. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give ethyl2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate(0.88 g, 76.5%) as crystals.

Melting point 201–202° C. Elemental analysis for C₃₀H₃₇N₃O₅S Calculated:C, 66.76; H, 6.48; N, 7.30. Found: C, 66.85; H, 6.56; N, 7.27.¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.37 (3H, t, J=7.0 Hz), 1.44(9H, s), 2.18–2.32 (1H, m), 2.71 (3H, s), 4.19 (2H, d, J=7.4 Hz), 4.22(2H, d, J=5.6 Hz), 4.33 (2H, q, J=7.0 Hz), 4.69 (1H, bs), 7.28–7.34 (2H,m), 7.46 (1H, d, J=1.6 Hz), 7.51–7.62 (3H, m), 8.00 (1H, dd, J=1.6, 8.4Hz), 8.49 (1H, d, J=8.4 Hz).

(3) Ethyl2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate(0.14 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized frommethanol-diisopropyl ether to give ethyl2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylatehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 286–287° C. Elemental analysis for C₂₇H₃₀N₃O₃ClS 0.25H₂OCalculated: C, 62.78; H, 5.95; N, 8.13. Found: C, 62.94; H, 6.35; N,8.11. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz) 1.29 (3H, t, J=7.2 Hz),2.02–2.21 (1H, m), 2.63 (3H, s), 3.90 (2H, s), 4.10 (2H, d, J=7.8 Hz),4.28 (2H, q, J=7.2 Hz), 7.44–7.52 (3H, m), 7.61–7.65 (3H, m), 8.14 (1H,dd, J=1.6, 8.4 Hz), 8.46 (1H, d, J=8.4 Hz), 8.59 (3H, bs)

Example 2152-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylicacid hydrochloride

(1) To a solution of ethyl2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate(0.69 g, 1.2 mmol) in tetrahydrofuran (10 ml) and ethanol (10 ml) wasadded 1N sodium hydroxide solution (3 ml). The resulting mixture wasstirred at room temperature for 2 h. The reaction mixture was pouredinto water, acidified with 1N hydrochloric acid and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas crystallized from ethyl acetate-n-hexane to give2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylicacid (0.61 g, 93.8%) as crystals.

Melting point 184–186° C. Elemental analysis for C₃₀H₃₃N₃O₅S Calculated:C, 65.79; H, 6.07; N, 7.67.Found: C, 65.60; H, 6.23; N, 7.46.¹-H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.50 (9H, s), 2.14–2.28 (1H,m), 2.67.(3H, s), 4.08 (2H, d, J=6.6 Hz), 4.17 (2H, s), 5.84 (1H, bs),7.38–7.44 (2H, m), 7.51–7.71 (5H, m), 8.28 (1H, d, J=8.8 Hz).

(2)2-(3-{[(Tert-butoxycarbonyl-)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylicacid (0.17 g, 0.3 mmol) was dissolved in a solution of 4N hydrogenchloride in ethyl acetate (5 ml). The solution was stirred at roomtemperature for 1 h. The reaction mixture was concentrated under reducedpressure, and the residue was crystallized from ethyl acetate to give2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl-]4-methyl-1,3-thiazole-5-carboxylicacid hydrochloride (0.12 g, 92.3%) as crystals.

Melting point 239–241° C. Elemental analysis for C₂₅H₂₆N₃O₃ClS H₂OCalculated: C, 59.82; H, 5.62; N, 8.37. Found: C, 59.64; H, 5.46; N,8.08. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.02–2.21 (1H, m), 2.61(3H, s), 3.91 (2H, s), 4.10 (2H, d, J=8.8 Hz), 7.44–7.49 (3H, m),7.61–7.66 (3H, m), 8.12 (1H, dd, J=1.4, 8.4 Hz), 8.45 (1H, d, J=8.4 Hz),8.64 (3H, bs).

Example 216 2-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxamidehydrochloride

(1) A solution of2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylicacid (0.44 g, 0.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.31 g, 1.6 mmol) and 1-hydroxybenzotriazole ammoniumsalt (0.24 g, 1.6 mmol) in N,N-dimethylformamide (10 ml) was stirred atroom temperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting crystals were recrystallized from ethylacetate-diisopropyl ether to givetert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.38 g, 86.4%) as crystals.

Melting point 227–228° C. Elemental analysis for C₃₀H₃₄N₄O₄S Calculated:C, 65.91; H, 6.27; N, 10.25. Found: C, 65.70; H, 6.19; N, 10.35.¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.4 Hz), 1.45 (9H, s), 2.12–2.31 (1H,m), 2.66 (3H, s), 4.08 (2H, d, J=7.4 Hz), 4.20 (2H, d, J=5.2 Hz), 5.00(1H, bs), 5.84 (2H, bs), 7.31–7.37 (3H, m), 7.52–7.61 (3H, m), 7.92 (1H,dd, J=1.6, 8.4 Hz), 8.41 (1H, d, J=8.4 Hz)

(2)Tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.14 g, 0.25 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure, and theresulting crystals were recrystallized from methanol-ethyl acetate togive2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxamidehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 222–224° C. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz),2.02–2.21 (1H, m), 2.56 (3H, s), 3.89 (2H, s), 4.10 (2H, d, J=6.4 Hz),7.42–7.49 (3H, m), 7.61–7.78 (5H, m), 8.09 (1H, d, J=8.6 Hz), 8.46 (1H,d, J=8.6 Hz), 8.54 (3H, bs).

Example 2172-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carbonitrilehydrochloride

(1) A solution oftert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.16 g, 0.3 mmol) and cyanuric chloride (0.17 g, 0.9 mmol) inN,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. Theresulting reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl[6-(5-cyano-4-methyl-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.15 g, 93.8%) as crystals.

Melting point 209–211° C. Elemental analysis for C₃₀H₃₂N₄O₃S Calculated:C, 68.16; H, 6.10; N, 10.60. Found: C, 68.17; H, 5.99; N, 10.70.¹H-NMR(CDCl₃) δ: 1.04 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.14–2.36 (1H,m), 2.61 (3H, s), 4.10 (2H, d, J=7.2 Hz), 4.23 (2H, d, J=5.4 Hz), 4.63(1H, bs), 7.27–7.32 (2H, m), 7.42 (1H, d, J=1.5 Hz), 7.53–7.60 (3H, m),7.97 (1H, dd, J=1.5, 8.4 Hz), 8.52 (1H, d, J=8.4 Hz).

(2)Tert-butyl[6-(5-cyano-4-methyl-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.21 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the residue was crystallized from ethyl acetate to give2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carbonitrilehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 284–285° C. Elemental analysis for C₂₅H₂₅N₄OClS 0.25H₂OCalculated: C, 63.95; H, 5.47; N, 11.93. Found: C, 64.00; H, 5.45; N,11.73. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.06–2.21 (1H, m),2.54 (3H, s), 3.89 (2H, s) 4.11 (2H, d, J=7.6 Hz), 7.44–7.49 (2H, m),7.52 (1H, d, J=1.5 Hz), 7.60–7.63 (3H, m), 8.11 (1H, dd, J=1.5, 8.4 Hz),8.48 (1H, d, J=8.4 Hz), 8.63 (3H, bs).

Example 218 Ethyl2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylatehydrochloride

(1) A solution of9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(2.33 g, 4 mmol) and ethyl 2-chloroacetate (1.32 g, 8 mmol) in ethanol(20 ml) was refluxed under heating for 10 h. The resulting reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography to give ethyl2-[4-butoxy-3-({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4methyl-1,3-thiazole-5-carboxylate(1.81 g, 65.3%) as crystals.

Melting point 203–204° C. Elemental analysis for C₄₀H₄₃N₃O₆S Calculated:C, 69.24; H, 6.25; N, 6.06. Found: C, 69.08; H, 6.11; N, 5.99.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 1.07 (3H, t, J=7.2 Hz), 1.42(3H, t, J=7.2 Hz), 1.58–1.75 (2H, m), 1.84–1.97 (2H, m), 2.04–2.23 (1H,m), 2.81 (3H, s), 3.92 (2H, t, J=6.4 Hz), 4.00 (2H, d, J=7.2 Hz), 4.23(1H, t, J=6.8 Hz), 4.39 (2H, q, J=7.2 Hz) 4.49 (2H, d, J=6.8 Hz), 4.59(2H, d, J=5.6 Hz), 5.29 (1H, bs), 7.28–7.43 (4H, m), 7.60 (2H, d, J=7.4Hz), 7.75 (2H, d, J=7.0 Hz), 8.05 (1H, dd, J=1.8, 8.4 Hz), 8.24 (1H, d,J=1.8 Hz), 8.44 (1H, d, J=8.4 Hz).

(2) To a solution of ethyl2-[4-butoxy-3({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylate(1.73 g, 2.5 mmol) in N,N-dimethylformamide (20 ml) and tetrahydrofuran(10 ml) was added pyrrolidine (2 ml). The resulting mixture was stirredat room temperature for 1 h. The reaction was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (20 ml), anddi-t-butyl dicarbonate (0.9 ml, 3.8 mmol) was added thereto. Theresulting mixture was stirred at room temperature for 1 h. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography to give ethyl2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate(1.15 g, 80.4%) as crystals.

Melting point 145.5–147° C. Elemental analysis for C₃₀H₄₁N₃O₆SCalculated: C, 63.02; H, 7.23; N, 7.35. Found: C, 63.00; H, 7.30; N,7.28. ¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 1.08 (3H, t, J=7.3 Hz),1.41 (3H, t, J=7.2 Hz), 1.47 (9H, s), 1.57–1.76 (2H, m), 1.85–1.99 (2H,m), 2.08–2.24 (1H, m), 2.81 (3H, s), 3.92 (2H, t, J=6.4 Hz), 4.00 (2H,d, J=7.8 Hz), 4.38 (2H, q, J=7.2 Hz), 4.54 (2H, d, J=5.6 Hz), 4.87 (1H,bs), 8.05 (1H, dd, J=1.8, 8.6 Hz), 8.26 (1H, d, J=1.8 Hz), 8.46 (1H, d,J=8.6 Hz).

(3) Ethyl2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate(0.17 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl; acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the residue was crystallized from ethyl acetate to give ethyl2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylatehydrochloride (0.14 g, 93.3%) as crystals.

Melting point 250–254° C. Elemental analysis for C₂₅H₃₄N₃O₄ClSCalculated: C, 59.10; H, 6.75; N, 8.27.Found: C, 58.90; H, 6.84; N,8.25. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.05 (3H, t, J=7.1 Hz),1.33 (3H, t, J=7.0 Hz), 1.57–1.76 (2H, m), 1.82–1.95 (2H, m), 1.00–2.18(1H, m), 2.74 (3H, s), 3.97–4.00 (4H, m), 4.21 (2H, s), 4.33 (2H, q,J=7.0 Hz), 8.18 (1H, d, J=8.4 Hz), 8.32 (1H, s), 8.39 (1H, d, J=8.4 Hz),8.67 (3H, bs).

Example 2192-[3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazaole-5-carboxylicacid hydrochloride

(1) To a solution of ethyl2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate(0.91 g, 1.6 mmol) in tetrahydrofuran (5 ml) and ethanol (5 ml) wasadded 1N sodium hydroxide solution (3 ml). The resulting mixture wasstirred at room temperature for 1 h. The reaction mixture was pouredinto water, acidified with 1N hydrochloric acid and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingcrystals were recrystallized from ethyl acetate-diisopropyl ether togive2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylicacid (0.78 g, 89.7%) as crystals.

Melting point 107–109° C. Elemental analysis for C₂₈H₃₇N₃O₆S 0.5H₂OCalculated: C, 60.85; H, 6.93; N, 7.60. Found: C, 60.73; H, 6.92; N,7.41. ¹H-NMR(CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.11 (3H, t, J=7.3 Hz),1.52 (9H, s), 1.60–1.78 (2H, m), 1.87–2.01 (2H, m), 2.04–2.21 (1H, m),2.82 (3H, s), 3.89–3.98 (4H, m), 4.54 (2H, d, J=4.8 Hz), 5.71 (1H, bs),7.91 (1H, d, J=8.3 Hz), 8.10 (1H, s), 8.29 (1H, d, J=8.3 Hz).

(2)2-(4-Butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylicacid (0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogenchloride in ethyl acetate (5 ml). The solution was stirred at roomtemperature for 1 h. The reaction mixture was concentrated under reducedpressure, and the residue was crystallized from ethyl acetate to give2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylicacid hydrochloride (0.13 g, 92.9%) as crystals.

Melting point 275–276° C. Elemental analysis for. Calcd forC₂₃H₃₀N₃O₄ClS 0.25H₂O Calculated: C, 57.01; H, 6.34; N, 8.67. Found: C,57.03; H, 6.28; N, 8.51. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.05(3H, t, J=7.4, Hz), 1.59–1.72 (2H, m), 1.83–1.91 (2H, m), 1.99–2.16 (1H,m), 2.72 (3H, s), 3.98–4.06 (4H, m), 4.21 (2H, s), 8.18 (1H, d, J=8.1Hz), 8.31 (1H, s) 8.39 (1H, d, J=8.1 Hz), 8.65 (3H, bs).

Example 2202-[3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxamidehydrochloride

(1) A solution of2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylicacid (0.60 g, 1.1 mmol), 1-ethyl,-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.42 g, 2.2 mmol) and 1-hydroxybenzotriazole ammoniumsalt (0.33 g, 2.2 mmol) in N,N-dimethylformamide (10 ml) was stirred atroom temperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to givetert-butyl{6-[5-(-aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.58 g, 96.7%) as crystals.

Melting point 233.5–234° C. Elemental analysis for C₂₈H₃₈N₄O₄SCalculated: C, 61.97; H, 7.06; N, 10.32. Found: C, 61.95; H, 7.07; N,10.19. ¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 1.07 (3H, t, J=7.3 Hz),1.49 (9H, s), 1.55–1.71 (2H, m), 1.80–1.98 (2H, m), 2.05–2.24 (1H, m),2.78 (3H, s), 3.91 (2H, t, J=6.4 Hz), 3.99 (2H, d, J=7.4 Hz), 4.53 (2H,d, J=5.0 Hz), 5.05 (1H, bs), 5.94 (2H, bs), 7.98 (1H, dd, J=1.6, 8.6Hz), 8.19 (1H, d, J=1.6 Hz), 8.42 (1H, d, J=8.6 Hz).

(2)Tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.22 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the residue was crystallized from ethyl acetate to give2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxamidehydrochloride (0.18 g, 94.7%) as crystals.

Melting point 270–271° C. Elemental analysis for C₂₃H₃₁N₄O₃ClSCalculated: C, 57.67; H, 6.52; N, 11.70. Found: 57.37; H, 6.46; N,11.62. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.05 (3H, t, J=7.1Hz), 1.56–1.74 (2H, m), 1.82–2.18 (3H, m), 2.67 (3H, s), 3.97–4.00 (4H,m), 4.21 (2H, s) 7.77 (2H, bs), 8.27 (1H, d, J=1.5 Hz), 8.39 (1H, dd,J=1.5, 8.4 Hz), 8.39 (1H, d, J=8.4 Hz), 8.66 (3H, bs).

Example 2212-[3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-carbonitrilehydrochloride

(1) A solution oftert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.33 g, 0.6 mmol) and cyanuric chloride (0.33 g, 1.8 mmol) inN,N-dimethylformamide (10 mmol) was stirred for 1 h at 0° C. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[4-butoxy-6-(5-cyano-4-methyl-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.25 g, 80.6%) as crystals.

Melting point 148.5–149.5° C. Elemental analysis for C₂₈H₃₆N₄O₄SCalculated: C, 64.10; H, 6.92; N, 10.68. Found: C, 64.04; H, 6.96; N,10.63. ¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.08 (3H, t, J=7.3 Hz),1.47 (9H, s), 1.57–1.75 (2H, m), 1.84–1.98 (2H, m), 2.08–2.28 (1H, m),2.72 (3H, s), 3.91 (2H, t, J=6.4 Hz), 4.01 (2H, d, J=7.4 Hz), 4.54 (2H,d, J=5.6 Hz), 4.80 (1H, bs), 8.02 (1H, dd, J=1.8, 8.2 Hz), 8.24. (1H, d,J=1.8 Hz), 8.48 (1H, d, J=8.2 Hz).

(2)Tert-butyl[4-butoxy-6-(5-cyano-4-methyl-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.21 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressureand the residue was crystallized from ethyl acetate-diisopropyl ether togive2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carbonitrilehydrochloride (0.17 g, 94.4%) as crystals.

Melting point 166–168° C. Elemental analysis for C₂₃H₂₉N₄O₂ClS 0.5H₂OCalculated: C, 58.77; H, 6.63; N, 11.92. Found: C, 58.58; H, 6.45; N,11.91. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.04 (3H, t, J=7.4Hz), 1.55–1.73 (2H, m), 1.82–1.95 (2H, m), 1.98–2.16 (1H, m), 2.66 (3H,s), 3.98–4.01 (4H, m), 4.22 (2H, s), 8.17 (1H, dd, J=8.4 Hz), 8.30 (1H,d, J=1.8 Hz), 8.42 (1H, d, J=8.4 Hz), 8.69 (3H, bs).

Example 2223-(Aminomethyl)-6-(4-amino-1,3-thiazol-2-yl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinonedihydrochloride

(1) A solution of2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1,3-thiazole-4-carboxylicacid (1.60 g, 3 mmol), diphenylphosphoryl azide (0.78 ml, 3.6 mmol) andtriethylamine (0.50 ml, 3.6 mmol) in N,N-dimethylformamide (10 ml) wasstirred at room temperature for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in toluene (20 ml) andrefluxed for 1 h. To the resulting mixture was added 9-fluorenylmethanol(0.88 g, 4.5 mmol), and the mixture was stirred at 100° C. for 3 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give9H-fluoren-9-ylmethyl2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1,3-thiazol-4-ylcarbamate(1.12 g, 51.4%) as an amorphous solid.

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.19–2.32 (1H,m), 4.07 (2H, d, J=6.6 Hz), 4.11–4.22 (3H, m), 4.45 (2H, s), 4.63 (1H,bs), 7.24–7.56 (13H, m), 7.77 (2H, d, J=7.5 Hz), 7.88 (1H, d, J=7.8 Hz),7.97 (1H, bs), 8.47 (1H, d, J=7.8 Hz).

(2) To a solution of 9H-fluoren-9-ylmethyl2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1,3-thiazol-4-ylcarbamate(1.09 g, 1.5 mmol) in N,N-dimethylformamide (20 ml) was addedpyrrolidine (1 ml). The mixture was stirred at room temperature for 1 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl[6-(4-amino-1,32-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.59 g, 78.7%) as crystals.

Melting point 195–196° C. Elemental analysis for C₂₈H₃₂N₄O₃S 0.25H₂OCalculated: C, 66.05; H, 6.43; N, 11.00 Found: C, 66.20; H, 6.54; N,10.96. ¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.43 (9H, s), 1.98–2.35(1H, m), 4.08 (2H, d, J=7.8 Hz), 4.14 (2H, bs), 4.21 (2H, d, J=5.8 Hz),4.58 (1H, bs), 5.95 (1H, s), 7.27–7.31 (2H, m), 7.42 (1H, d, J=1.6 Hz),7.48–7.59 (3H, m), 7.91 (1H, dd, J=1.6, 8.2 Hz), 8.47 (1H, d, J=8.2 Hz).

(3)Tert-butyl[6-(4-amino-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.14 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure, and theresidue was crystallized from ethyl acetate to give3-(aminomethyl)-6-(4-amino-1,3-thiazol-2yl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinonedihydrochloride (0.13 g, 92.9%) as crystals.

Melting point 230° C. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.2 Hz),1.99–2.21 (1H, m), 3.87 (2H, s), 4.10 (2H, d, J=8.2 Hz), 5.48 (3H, bs),7.10 (1H, s), 7.16–7.62 (6H, m), 8.03 (1H, d, J=8.4 Hz), 8.44 (1H, d,J=8.4 Hz), 8.67 (3H, bs).

Example 223N-{2-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazol-4-yl}acetamidehydrochloride

(1) A solution oftert-butyl[6-(4-amino-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.20 g, 0.4 mmol) and acetyl chloride (0.04 ml, 0.6 mmol) inN,N-dimethylacetamide (10 ml) was stirred at room temperature for 2 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to givetert-butyl{6-[4-(acetylamino)-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.18 g, 85.7%) as crystals.

Melting point 227–228° C. Elemental analysis for C₃₀H₃₄N₄O₄S Calculated:C, 65.91; H, 6.27; N, 10.25. Found: C, 65.66; H, 6.44; N, 10.17.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.47 (9H, s), 2.18–2.39 (4H,m), 4.10 (2H, bs), 4.19 (2H, bs), 7.06–7.38 (4H, m), 7.41–7.56 (3H, m),7.61 (1H, s), 8.13 (1H, bs), 8.69 (1H, bs).

(2)Tert-butyl{6-[4-(acetylamino)-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.14 g, 0.25 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure, and theresidue was crystallized from ethyl acetate to giveN-{2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazol-4-yl}acetamidehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 242–244° C. Elemental analysis for C₂₅H₂₇N₄O₂ClS 2H₂OCalculated: C, 57.85; H, 6.02; N, 10.79. Found: C, 57.70; H, 5.69; N,10.69. ¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 1.99–2.18 (4H, m),3.86 (2H, s), 4.10 (2H, d, J=6.3 Hz), 7.45–7.48 (3H, m), 7.54–7.66 (4H,m), 8.05 (1H, d, J=8.6 Hz), 8.46 (1H, d, J=8.6 Hz), 8.65 (3H, bs), 11.03(1H, s)

Example 224 Methyl2-{[3-(aminomethyl)-2-isobutyl-1oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-oxy}-2-methylpropanoatehydrochloride

(1) To a solution oftert-butyl[6-hydroxy-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.42 g, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodiumhydride (48 mg, 1.2 mmol) (60% in oil). The resulting mixture wasstirred at 0° C. for 10 min. To the mixture was added methyl2-bromoisobutyrate (0.22 g, 1.2 mmol), and the mixture was stirred atroom temperature for 12 h. The reaction mixture was poured into waterand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give methyl2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoate(0.31 g, 59.6%) as crystals.

Melting point 207–209° C. Elemental analysis for C₃₀H₃₈N₂O₆ 0.25H₂OCalculated: C, 68.35; H, 7.36; N, 5.31. Found: C, 68.39; H, 7.54; N,5.31. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.42 (9H, s), 1.51 (6H,s), 2.11–2.31 (1H, m) 3.53 (3H, s) 4.04 (2H, d, J=7.4 Hz), 4.18 (2H, d,J=5.4 Hz), 4.42 (1H, bs), 6.14 (1H, d, J=2.5 Hz), 6.94 (1H, dd, J=2.5,8.8 Hz), 7.19–7.24 (2H, m), 7.46–7.57 (3H, m), 8.35 (1H, d, J=8.8 Hz).

(2) Methyl2-[(3-{[(tert-butoxycarbonyl)amino]methyl-}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoate(0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure, and theprecipitated crystals were recrystallized from ethyl acetate-diisopropylether to give methyl2-{[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}-2-methylpropanoatehydrochloride(0.10 g, 71.4%) as crystals.

Melting point 236–237° C. Elemental analysis for C₂₅H₃₁N₂O₄Cl 1.25H₂OCalculated: C, 62.36; H, 7.01; N, 5.82. Found: C, 62.32; H, 6.73; N,5.58. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz) 1.44 (6H, s), 1.99–2.18(1H, m), 3.45 (3H, s), 3.84 (2H, s), 4.05 (2H, d, J=7.0 Hz), 5.99 (1H,d, J=2.4 Hz), 7.02 (1H, dd, J=2.4, 8.8 Hz), 7.34–7.39 (2H, m), 7.55–7.62(3H, m), 8.23 (1H, d, J=8.8 Hz), 8.57 (3H, bs).

Example 2252-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}-2-methylpropanoicacid hydrochloride

(1) To a solution of methyl2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoate(0.37 g, 0.7 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) wasadded 1N sodium hydroxide solution (2 ml). The mixture was stirred atroom temperature for 1 h. The reaction mixture was poured into wateracidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting crystalswere crystallized from ethyl acetate-diisopropyl ether to give2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoicacid (0.32 g, 91.4%) as crystals.

Melting point 219–220° C. Elemental analysis for C₂₉H₃₆N₂O₆ Calculated:C, 68.48; H, 7.13; N, 5.51. Found: C, 68.48; H, 7.19; N, 5.28.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.42 (9H, s), 1.59 (6H, s),2.16–2.32 (1H, m), 4.07 (2H, d, J=7.4 Hz), 4.19 (2H, d, J=5.2 Hz), 4.58(1H, bs), 6.41 (1H, d, J=2.4 Hz), 6.97 (1H, dd, J=2.4, 8.8 Hz),7.14–7.22 (2H, m), 7.41–7.56 (3H, m), 8.30 (1H, d, J=8.8 Hz).

(2)2-[(3-{[(Tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoicacid (0.13 g, 0.25 mmol) was dissolved in a solution of 4N hydrogenchloride in ethyl acetate (5 ml). The solution was stirred at roomtemperature for 1 h. The reaction mixture was concentrated under reducedpressure, and the residue was crystallized from ethyl acetate to give2-{[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}-2-methylpropanoicacid hydrochloride (0.10 g, 90.9%) as crystals.

Melting point 256–257° C. Elemental analysis for C₂₄H₂₉N₂O₄Cl 0.5H₂OCalculated: C, 63.50; H, 6.66; N, 6.17. Found: C, 63.25; H, 6.66; N,5.86. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz) 1.44 (6H, s), 1.99–2.14(1H, m), 3.86 (2H, s), 4.03 (2H, d, J=6.9 Hz), 6.17 (1H, d, J=2.2 Hz),7.01 (1H, dd, J=2.2, 8.7 Hz), 7.34–7.37 (2H, m), 7.49–7.58 (3H, m), 8.22(1H, d, J=8.7 Hz), 8.49 (3H, bs).

Example 2262-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}-2-methylpropanamidehydrochloride

(1) A solution of2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoicacid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammoniumsalt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred atroom temperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting crystals were recrystallized from ethylacetate-diisopropyl ether to givetert-butyl[6-(2-amino-1,1-dimethyl-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.19 g, 95.0%) as crystals.

Melting point 219–220° C. Elemental analysis for C₂₉H₃₇N₃O₅ 0.25H₂OCalculated: C, 68.01; H, 7.38; N, 8.21. Found: C, 68.04; H, 7.46; N,7.97. ¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.4 Hz), 1.42 (9H, s), 1.46 (6H,s), 2.12–2.31 (1H, m), 4.05 (2H, d, J=7.2 Hz), 4.20 (2H, d, J=5.4 Hz),4.45 (1H, bs), 5.36 (1H, bs), 6.34 (1H, bs), 6.39 (1H, d, J=2.6 Hz),7.03 (1H, dd, J=2.6, 8.8 Hz), 7.20–7.25 (2H, m), 7.48–7.58 (3H, m), 8.39(1H, d, J=8.8 Hz).

(2)Tert-butyl[6-(2-amino-1,1-dimethyl-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure, and theresidue was crystallized from ethyl acetate to give2-{[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}-2-methylpropanamidehydrochloride (0.12 g, 92.3%) crystals.

Melting point 182–184° C. Elemental analysis for C₂₄H₃₀N₃O₃Cl AcOEtCalculated: C, 63.21; H, 7.20; N, 7.90. Found: C, 63.31; H, 7.47; N,8.11. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.38 (6H, s), 1.99–2.18(1H, m), 3.85 (2H, s), 4.04 (2H, d, J=6.8 Hz), 6.27 (1H, d, J=2.2 Hz),7.04 (1H, dd, J=2.2, 8.8 Hz), 7.17 (1H, bs), 7.34–7.38 (2H, m), 7.44(1H, bs), 7.54–7.61 (3H, m), 8.22 (1H, d, J=8.8 Hz), 8.55 (3H, bs).

Example 2276-Acetyl-3-(aminomethyl)-4-butoxy-2-isobutyl-1(2H)-isoquinolinonehydrochloride

(1) A solution of4-butoxy-3{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (4.46 g, 10 mmol), N,O-dimethylhydroxyamine hydrochloride (1.17 g,12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(2.30 g, 12 mmol), 1-hydroxybenzotriazole (1.84 g, 12 mmol) andtriethylamine (1.7 ml, 12 mmol) in N,N-dimethylformamide (10 ml) wasstirred at room temperature for 2 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting crystals were recrystallized from ethylacetate-diisopropyl ether to givetert-butyl(4butoxy-2-isobutyl-6-{[methoxy(methyl)amino]carbonyl}-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(4.15 g, 84.9%) as crystals.

Melting point 142–143° C. Elemental analysis for C₂₆H₃₉N₃O₆ Calculated:C, 63.78; H, 8.03; N, 8.58. Found: C, 63.59; H, 8.10; N, 8.58.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.9 Hz), 1.02 (3H, t, J=7.0 Hz), 1.47(9H, s), 1.48–1.62 (2H, m), 1.79–1.93 (2H, m), 2.12–2.26 (1H, m), 3.41(3H, s), 3.54 (3H, s), 3.88 (2H, t, J=6.5 Hz), 4.01 (2H, d, J=7.6 Hz),4.53 (2H, d, J=5.6 Hz), 4.74 (1H, bs), 7.74 (1H, dd, J=1.4, 8.6 Hz),7.99 (1H, d, J=1.4 Hz), 8.46 (1H, d, J=8.6 Hz).

(2) To a solution oftert-butyl(4-butoxy-2-isobutyl-6{[methoxy(methyl)amino]carbonyl}-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.49 g, 1 mmol) in tetrahydrofuran (10 ml) was added 1N methylmagnesiumbromide tetrahydrofuran solution (5 ml) at 0° C. The mixture was stirredat 0° C. for 1 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto givetert-butyl(6-acetyl-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.37 g, 84.1%) as crystals.

Melting point 161–162° C. Elemental analysis for C₂₅H₃₆N₂O₅ Calculated:C, 67.54; H, 8.16; N, 6.30. Found: C, 67.30; H, 8.14; N, 6.21.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 1.06 (3H, t, J=7.2 Hz), 1.47(9H, s), 1.53–1.72 (2H, m), 1.82–1.97 (2H, m), 2.12–2.25 (1H, m), 2.71(3H, s), 3.90 (2H, t, J=6.5 Hz), 4.01 (2H, d, J=7.4 Hz), 4.54 (2H, d,J=5.6 Hz), 4.78 (1H, bs), 8.01 (1H, dd, J=2.0, 8.4 Hz), 8.28 (1H, d,J=2.0 Hz), 8.49 (1H, d, J=8.4 Hz).

(3)Tert-butyl(6-acetyl-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.13 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure, and theprecipitated crystals were recrystallized from methanol-diisopropylether to give6-acetyl-3-(aminomethyl)-4-butoxy-2-isobutyl-1(2H)-isoquinolinonehydrochloride (0.10 g, 90.9%) as crystals.

Melting point 171.5–173° C. Elemental analysis for C₂₀H₂₉N₂O₃ClCalculated: C, 63.06; H, 7.67; N, 7.35. Found: C, 62.77; H, 7.77; N,7.26. ¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.4 Hz),1.52–1.70 (2H, m), 1.84–2.16 (3H, m), 2.72 (3H, s), 3.92–4.01 (4H, m),4.20 (2H, s), 8.12 (1H, d, J=8.2 Hz), 8.26 (1H, s), 8.39 (1H, d, J=8.2Hz), 8.70 (3H, bs).

The compounds of following Examples 228 to 252 were synthesizedaccording to the method similar to that in Example 214 (2) from theN-Boc intermediates.

Example 228(E)-3-[3-(Aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenoicacid hydrochloride

Melting point 268–270° C. Elemental analysis for C₂₃H₂₄N₂O₃Cl₂ 0.5H₂OCalculated: C, 60.53; H, 5.52; N, 6.14. Found: C, 60.49; H, 5.75; N,5.81. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 2.04–2.18 (1H, m), 3.86(2H, s), 4.07 (2H, d, J=6.6 Hz), 6.52 (1H, d, J=15.9 Hz), 7.09 (1H, s),7.44 (2H, d, J=8.1 Hz), 7.56 (1H, d, J=15.9 Hz), 7.64 (2H, d, J=8.1 Hz),7.96 (1H, d, J=8.7 Hz), 8.33 (1H, d, J=8.7 Hz), 8.53 (3H, bs).

Example 229 Methyl3-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride

Melting point 177–179° C. Elemental analysis for C₂₂H₂₄N₂O₃Cl₂ 0.25H₂OCalculated: C, 60.07; H, 5.61; N, 6.37. Found: C, 60.00; H, 5.89; N,6.24. ¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.02–2.18 (1H, m), 3.82(3H, s), 3.88 (2H, s), 4.08 (2H, d, J=7.0 Hz), 7.46 (2H, d, J=8.4 Hz),7.61 (1H, d, J=1.6 Hz), 7.68 (2H, d, J=8.4 Hz), 8.08 (1H, dd, J=1.6, 8.4Hz), 8.46 (1H, d, J=8.4 Hz), 8.52 (3H, bs).

Example 230(Aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid hydrochloride

Melting point 263–265° C. ¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz),1.99–2.18 (1H, m), 3.88 (2H, s), 4.08 (2H, d, J=7.0 Hz), 7.46 (2H, d,J=8.4 Hz), 7.51 (1H, d, J=1.4 Hz), 7.67 (2H, d, J=8.4 Hz), 8.06 (1H, dd,J=1.4, 8.2 Hz), 8.44 (1H, d, J=8.2 Hz), 8.46 (3H, bs).

Example 2313-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarbothioamidehydrochloride

Melting point 257–259° C. Elemental analysis for C₂₁H₂₄N₃OClS 0.5H₂OCalculated: C, 61.37; H, 6.13; N, 10.22. Found: C, 61.04; H, 5.99; N,9.85. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 1.99–2.18 (1H, m), 3.88(2H, s), 4.06 (2H, d, J=7.2 Hz), 7.37–7.43 (3H, m), 7.56–7.59 (3H, m),7.85 (1H, dd, J=1.5, 8.4 Hz), 8.32 (1H, d, J=8.4 Hz), 8.52 (3H, bs),9.67 (1H, bs), 10.02 (1H, bs).

Example 2323-(Aminomethyl)-6-(benzyloxy)-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinonehydrochloride

Melting point 162–164° C. Elemental analysis for C₂₇H₂₈N₂O₃Cl₂ 0.25H₂OCalculated: C, 66.46; H, 5.89; N, 5.74. Found: C, 66.26; H, 5.87; N,5.49. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.98–2.13 (1H, m), 3.82(2H, s), 4.03 (2H, d, J=7.0 Hz), 5.04 (2H, s), 6.26 (1H, d, J=2.6 Hz),7.23–7.59 (8H, m), 7.61 (2H, d, J=8.4 Hz), 8.25 (1H, d, J=8.8 Hz), 8.52(3H, bs).

Example 2333-(Aminomethyl)-4-(4-chlorophenyl)-6-hydroxy-2-isobutyl-1(2H)-isoquinolinonehydrochloride

Melting point 247–249° C. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=7.0 Hz),1.99–2.13 (1H, m), 3.82 (2H, s), 3.99 (2H, d, J=7.4 Hz), 6.19 (1H, d,J=2.2 Hz), 6.99 (1H, dd, J=2.2, 8.8 Hz), 7.40 (2H, d, J=8.4 Hz), 7.63(2H, d, J=8.4 Hz), 8.16 (1H, d, J=8.8 Hz), 8.42 (3H, bs), 10.30 (1H, s).

Example 234(E)-3-[3-(Aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenoicacid hydrochloride

Melting point 230–231° C. Elemental analysis for C₂₅H₂₇N₂O₃Cl H₂OCalculated: C, 64.78; H, 6.57; N, 6.30. Found: C, 64.73; H, 6.63; N,5.86. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 2.06–2.18 (1H, m), 2.45(3H, s), 3.89 (2H, s), 4.07 (2H, d, J=6.6 Hz), 6.47 (1H, d, J=16.0 Hz),7.05 (1H, d, J=1.2 Hz), 7.29 (2H, d, J=8.1 Hz), 7.40 (2H, d, J=8.1 Hz),7.49 (1H, d, J=16.0 Hz), 7.94 (1H, dd, J=1.2, 8.1 Hz), 8.33 (1H, d,J=8.1 Hz), 8.50 (3H, bs).

Example 235 Methyl3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride

Melting point 254–256° C. Elemental analysis for C₂₃H₂₇N₂O₃Cl 0.25H₂OCalculated: C, 65.86; H, 6.61; N, 6.68. Found: C, 66.03; H, 6.67; N,6.50. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 2.06–2.16 (1H, m), 2.45(3H, s), 3.81 (3H, s), 3.89 (2H, s), 4.10 (2H, d, J=6.9 Hz), 7.31 (2H,d, J=7.8 Hz), 7.41 (2H, d, J=7.8 Hz), 7.57 (1H, s), 8.06 (1H, d, J=8.3Hz), 8.45 (1H, d, J=8.3 Hz), 8.57 (3H, bs).

Example 236

3-(Aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid hydrochloride

Melting point 259–261° C. Elemental analysis for C₂₂H₂₅N₂O₃Cl 0.75 H₂OCalculated: C, 63.76; H, 6.45; N, 6.76. Found: C, 63.66; H, 6.49; N,6.50. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 1.99–2.14 (1H, m), 2.45(3H, s), 3.89 (2H, s), 4.09 (2H, d, J=7.4 Hz), 7.31 (2H, d, J=7.9 Hz),7.42 (2H, d, J=7.9 Hz), 7.57 (1H, d, J=1.4 Hz), 8.05 (1H, dd, J=1.4, 8.4Hz), 8.43 (1H, d, J=8.4 Hz), 8.53 (3H, bs).

Example 2373-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarbothioamidehydrochloride

Melting point 200–202° C. ¹H-NMR(DMSO-d6) δ: 0.88 (6H, d, J=6.6 Hz),1.00 (3H, t, J=7.3 Hz), 1.49–1.67 (2H, m), 1.79–2.08 (3H, m), 3.95–4.01(4H, m), 4.19 (2H, bs), 7.98 (1H, dd, J=1.5, 8.5 Hz), 8.20 (1H, d, J=1.5Hz), 8.28 (1H, d, J=8.5 Hz), 8.51 (3H, bs), 9.87 (1H, bs), 10.20 (3H,bs).

Example 2383-(Aminomethyl)-6-(benzyloxy)-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinonehydrochloride

Melting point 244–246° C. Elemental analysis for C₂₈H₃₁N₂O₂ClCalculated: C, 72.63; H, 6.75; N, 6.05. Found: C, 72.31; H, 6.84; N,5.93. ¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.98–2.18 (1H, m), 2.43(3H, s), 3.84 (2H, s), 4.02 (2H, d, J=7.4 Hz), 5.01 (2H, s), 6.31 (1H,d, J=2.2 Hz), 7.18–7.38 (10H, m), 8.24 (1H, d, J=8.8 Hz), 8.45 (3H, bs).

Example 2393-(Aminomethyl)-6-hydroxy-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinonehydrochloride

Melting point 255–256° C. ¹H-NMR(DMSO-d6) δ: 0.90 (6H, d, J=7.0 Hz),1.99–2.13 (1H, m), 2.42 (3H, s), 3.83 (2H, s), 4.02 (2H, d, J=7.4 Hz),6.23 (1H, d, J=2.4 Hz), 6.99 (1H, d, J=2.4, 8.6 Hz), 7.25 (2H, d, J=8.1Hz), 7.37 (2H, d, J=8.1 Hz), 8.15 (1H, d, J=8.6 Hz), 8.50 (3H, bs),10.27 (1H, s).

Example 240(E)-3-[3-(Aminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenoicacid hydrochloride

Melting point 255–256° C. ¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz),1.99–2.18 (1H, m), 3.87 (2H, s), 4.08 (2H, d, J=7.0 Hz), 6.50 (1H, d,J=16.2 Hz), 7.07 (1H, d, J=1.2 Hz), 7.36–7.48 (4H, m), 7.55 (1H, d,J=16.2 Hz), 7.95 (1H, dd, J=1.2, 8.0 Hz), 8.33 (1H, d, J=8.0 Hz), 8.59(3H, bs).

Example 2413-(Aminomethyl)-6-(benzyloxy)-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinonehydrochloride

Melting point 226–227° C. Elemental analysis for C₂₇H₂₈N₂O₂ClFCalculated: C, 69.44; H, 6.04; N, 6.00. Found: C, 69.44; H, 5.89; N,6.12. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.99–2.14 (1H, m), 3.83(2H, s), 4.04 (2H, d, J=7.4 Hz), 5.04 (2H, s), 6.26 (1H, d, J=2.6 Hz),7.23–7.44 (10H, m), 8.25 (1H, d, J=8.8 Hz), 8.56 (3H, bs).

Example 2423-(Aminomethyl)-4-(4-fluorophenyl)-6-hydroxy-2-isobutyl-1(2H)-isoquinolinonehydrochloride

Melting point 249–251° C. Elemental analysis for C₂₀H₂₂N₂O₂ClF 1.5H₂OCalculated: C, 59.48; H, 6.24; N, 6.94. Found: C, 59.21; H, 5.99; N,6.68. ¹H-NMR(-DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz) 1.98–2.16 (1H, m), 3.82(2H, d, J=7.0 Hz), 4.03 (2H, d, J=7.0 Hz), 6.19 (1H, d, J=2.2 Hz), 6.98(1H, bs), 7.01 (1H, d, J=2.2, 8.8 Hz) 7.34–7.48 (4H, m), 8.16 (1H, d,J=8.8 Hz), 8.61 (3H, bs).

Example 243 Methyl3-(aminomethyl)-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride

Melting point 177–179° C. Elemental analysis for C₂₂H₂₄N₂O₃ClF 0.5H₂OCalculated: C, 61.75; H, 5.89; N, 6.55. Found: C, 61.55; H, 6.04; N,6.34. ¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.04–2.18 (1H, m), 3.81(3H, s), 3.89 (2H, s), 3.89 (2H, d, J=7.8 Hz), 7.27–7.47 (3H, m), 7.51(1H, d, J=1.3 Hz), 7.62–7.70 (1H, m), 8.08 (1H, dd, J=1.3, 8.4 Hz), 8.46(1H, d, J=8.4 Hz), 8.59–8.67 (3H, m).

Example 2443-(Aminomethyl)-4-(3-fluorphenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid hydrochloride

Melting point 252–254° C. Elemental analysis for C₂₁H₂₂N₂O₃ClF 0.75H₂OCalculated: C, 60.29; H, 5.66; N, 6.70. Found: C, 60.29; H, 5.97; N,6.53. ¹H-NMR(DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 1.99–2.18 (1H, m), 3.89(2H,bs), 4.04–4.17 (2H, m), 7.27–7.52 (4H, m), 7.60–7.71 (1H, m), 8.06(1H, dd, J=1.2, 8.4 Hz), 8.44 (1H, d, J=8.4 Hz), 8.63 (3H, bs).

Example 2453-(Aminomethyl)-6-(benzyloxy)-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinonehydrochloride

Melting point 178–180° C. Elemental analysis for C₂₇H₂₈N₂O₂ClF 0.25H₂OCalculated: C, 68.78; H, 6.09; N, 5.94. Found: C, 68.57; H, 6.20; N,5.84. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.99–2.11 (1H, m),3.77–3.90 (2H, m), 3.96–4.13 (2H, m), 5.04 (2H, s), 6.26 (1H, d, J=2.4Hz), 7.16–7.43 (9H, m), 7.57–7.65 (1H, m), 8.25 (1H, d, J=8.7 Hz), 8.60(3H, bs).

Example 2463-(Aminomethyl)-4-(3-fluorophenyl)-6-hydroxy-2-isobutyl-1(2H)-isoquinolinonehydrochloride

Melting point 226–227° C. Elemental analysis for C₂₀H₂₂N₂O₂ClF 1.5H₂OCalculated: C, 59.48; H, 6.24; N, 6.94. Found: C, 59.28; H, 6.09; N,6.85. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.98–2.12 (1H, m), 3.82(2H, bs), 3.92–4.14 (2H, m), 6.20 (1H, d, J=2.4 Hz), 7.02 (1H, d, J=2.4,8.6 Hz), 7.20–7.41 (3H, m), 7.56–7.67 (1H, m), 8.16 (1H, d, J=8.6 Hz),8.60 (3H, bs).

Example 247 Methyl{[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}acetatehydrochloride

Melting point 228–229° C. Elemental analysis for C₂₃H₂₇N₂O₄Cl 0.25H₂OCalculated: C, 63.44; H, 6.37; N, 6.43. Found: C, 63.53; H, 6.27; N,6.30. ¹H-NMR(DMSO-d₆) δ: 0.91(6H, d, J=6.6 Hz), 1.99–2.18 (1H, m), 3.60(3H, s), 3.86 (2H, s), 4.04 (2H, d, J=7.2 Hz), 4.71 (2H, s), 6.13 (1H,d, J=2.4 Hz), 7.20 (1H, dd, J=2.4, 8.8 Hz), 7.34–7.39 (2H, m), 7.54–7.60(3H, m), 8.26 (1H, d, J=8.8 Hz), 8.47 (3H, bs).

Example 248{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}aceticacid hydrochloride

Melting point 255–257° C. Elemental analysis for C₂₂H₂₅N₂O₄Cl 0.5H₂OCalculated: C, 62.04; H, 6.15; N, 6.58. Found: C, 62.15; H, 6.28; N,6.36. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.99–2.18 (1H, m), 3.86(2H, s), 4.05 (2H, d, J=7.6 Hz), 4.61 (2H, s), 6.20 (1H, d, J=2.2 Hz),7.18 (1H, dd, J=2.2, 8.8 Hz), 7.35–7.40 (2H, m), 7.52–7.63 (3H, m), 8.26(1H, d, J=8.8 Hz), 8.55 (3H, bs).

Example 249 Methyl3-(aminomethyl)-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride

Melting point 243–245° C. Elemental analysis for C₂₂H₂₄N₂O₃ClF 1.0H₂OCalculated: C, 63.23; H, 6.27; N, 6.70. Found: C, 63.08; H, 5.89; N,6.46. ¹H-NMR(DMSO-d₆) δ: 0.92 (3H, d, J=6.3 Hz), 0.94 (3H, d, J=5.7 Hz),2.04–2.18 (1H, m), 3.77–3.80 (1H, m), 3.81 (3H, s), 3.97–4.05 (2H, m),4.13–4.21 (1H, m), 7.44–7.58 (4H, m), 7.64–7.72 (1H, m), 8.10 (1H, dd,J=1.6, 8.7 Hz), 8.48 (1H, d, J=8.7 Hz), 8.66 (3H, bs).

Example 2503-(Aminomethyl)-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid hydrochloride

Melting point 222–224° C. Elemental analysis for C₂₁H₂₂N₂O₃ClF 0.75H₂OCalculated: C, 60.29; H, 5.66; N, 6.70. Found: C, 60.37; H, 5.76; N,6.31. ¹H-NMR(DMSO-d₆) δ: 0.92 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz),2.05–2.17 (1H, m), 3.77–3.84 (1H, m), 3.95–4.22 (3H, m), 7.42–7.73 (5H,m), 8.08 (1H, dd, J=1.4, 8.2 Hz), 8.45 (1H, d, J=8.2 Hz), 8.66 (3H, bs).

Example 2513-(Aminomethyl)-6-(benzyloxy)-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinonehydrochloride

Melting point 144–145° C. Elemental analysis for C₂₇H₂₈N₂O₂ClF 0.5H₂OCalculated: C, 68.13; H, 6.14; N, 5.89. Found: C, 68.08; H, 6.43; N,5.83. ¹H-NMR(DMSO-d₆) δ: 0.89 (3H, d, J=6.6 Hz), 0.91 (3H, d, J=6.6 Hz),1.99–2.16 (1H, m), 3.69–4.18 (4H, m), 5.04 (2H, s), 6.26 (1H, d, J=2.0Hz), 7.22–7.47 (9H, m), 7.59–7.68 (1H, m), 8.26 (1H, d, J=8.8 Hz), 8.52(3H, bs).

Example 2523-(Aminomethyl)-4-(2-fluorophenyl)-6-hydroxy-2-isobutyl-1(2H)-isoquinolinonehydrochloride

Melting point 259–260° C. Elemental analysis for C₂₀H₂₂N₂O₂ClCalculated: C, 63.74; H, 5.88; N, 7.43. Found: C, 63.38; H, 5.71; N,7.43. ¹H-NMR(DMSO-d₆) δ: 0.89 (3H, d, J=6.6 Hz), 0.91 (3H, d, J=6.6 Hz),2.01–2.18 (1H, m), 3.68–4.16 (4H, m), 6.20 (1H, d, J=2.4 Hz), 7.02 (1H,dd, J=2.4, 8.6 Hz), 7.37–7.67 (4H, m), 8.17 (1H, d, J=8.6 Hz), 8.55 (3H,bs), 10.37 (3H, bs).

Example 2533-(Aminomethyl)-6-(benzyloxy)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinonehydrochloride

(1) A mixture of methyl6-(benzyloxy)-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(10.26 g, 20 mmol), 2-thiopheneboronic acid (3.07 g, 24 mmol), sodiumcarbonate (5.30 g, 50 mmol), toluene (50 ml), methanol (10 ml) and water(10 ml) was stirred at room temperature for 30 min under an argonatmosphere. To the resulting mixture was addedtetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol), the mixture wasrefluxed under heating for 10 h under an argon atmosphere. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography to give methyl6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylate(2.11 g, 23.6%) as crystals.

Melting point 143–144° C. Elemental analysis for C₂₆H₂₅NO₄S Calculated:C, 69.78; H, 5.63; N, 3.13. Found: C, 69.77; H, 5.76; N, 3.15.¹H-NMR(CDCl₃) δ: 0.92 (6H, d, J=7.0 Hz), 2.05–2.21 (1H, m), 3.59 (3H,s), 3.92 (2H, d, J=7.8 Hz), 5.02 (2H, s), 6.85 (1H, d, J=2.6 Hz), 6.98(1H, dd, J=1.2, 3.4 Hz), 7.10 (1H, dd, J=3.4, 5.1 Hz), 7.17 (1H, dd,J=2.4, 9.1 Hz), 7.29–7.42 (5H, m), 7.46 (1H, dd, J=1.2, 5.1 Hz), 8.39(1H, d, J=9.1 Hz).

(2) To a suspension of methyl6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylate(2.01 g, 4.5 mmol) in methanol (30 ml) was added a solution of lithiumhydroxide monohydrate (0.57 g, 13.5 mmol) in water (10 ml). Theresulting mixture was refluxed under heating for 48 h. The reactionmixture was poured into water, acidified with 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting crystals were recrystallized from ethylacetate-n-hexane to give6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylicacid (1.71 g, 87.7%) as crystals.

Melting point 171–172° C. Elemental analysis for C₂₅H₂₃NO₄S 0.3H₂OCalculated: C, 68.41; H, 5.42; N, 3.19. Found: C, 68.51; H, 5.84; N,2.93. ¹H-NMR(CDCl₃) δ: 0.87 (6H, d, J=6.6 Hz), 2.13–2.26 (1H, m), 3.89(2H, d, J=7.4 Hz), 5.00 (2H, s), 6.79 (1H, d, J=1.8 Hz), 7.08–7.13 (3H,m), 7.27–7.45 (5H, m), 7.46–7.48 (1H, m), 8.26 (1H, dd, J=1.4, 9.0 Hz).

(3) To a solution of6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylicacid (1.52 g, 3.5 mmol) in tetrahydrofuran (20 ml) were added oxalylchloride (0.37 ml, 4.2 mmol) and N,N-dimethylformamide (2 drops). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 ml). The solution was added dropwise toa suspension of sodium tetrahydroborate (0.47 g, 12.3 mmol) in1,2-dimethoxyethane (20 ml) at 0° C., and the mixture was stirred at 0°C. for 1 h. The reaction mixture was poured into 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give6-(benzyloxy)-3-(hydroxymethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone(1.36 g, 92.5%) as crystals.

Elemental analysis for C₂₅H₂₅NO₃S Calculated: C, 71.57; H, 6.01; N,3.34. Found: C, 71.32; H, 6.08; N, 3.25. ¹H-NMR(CDCl₃) δ: 0.96 (6H, d,J=7.0 Hz), 2.11–2.35 (1H, m), 4.18 (2H, d, J=7.4 Hz), 4.53 (2H, d, J=6.2Hz), 4.94 (2H, s), 6.55 (1H, d, J=2.2 Hz), 7.00–7.05 (2H, m), 7.18 (1H,dd, J=3.5, 5.2 Hz), 7.23–7.38 (5H, m), 7.48 (1H, dd, J=1.0, 5.2 Hz),8.30 (1H, d, J=9.0 Hz).

(4) To a suspension of6-(benzyloxy)-3-(hydroxymethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone(1.26 g, 3 mmol) in toluene (20 ml) was added thionyl chloride (0.44 ml,6 mmol). The resulting mixture was refluxed for 2 h. The reactionmixture was added to a saturated sodium hydrogen carbonate solution andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reduced pressureto give6-(benzyloxy)-3-(chloromethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone(1.30 g, 100%) as an oil.

¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 2.12–2.31 (1H, m), 4.14 (2H,bs), 4.48 (2H, s), 4.99 (2H, s), 6.61 (1H, d, J=2.6 Hz) 7.05 (1H, dd,J=1.6, 3.5 Hz), 7.11–7.38 (7H, m), 7.51 (1H, dd, J=1.6, 5.1 Hz), 8.38(1H, d, J=8.8 Hz).

(5) A solution of6-(benzyloxy)-3-(chloromethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone(1.31 g, 3 mmol) and potassium phthalimide (0.83 g, 4.5 mmol) inN,N-dimethylformamide (20 ml) was stirred at room temperature for 3 h.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give2-{[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione(1.42 g, 86.6%) as an amorphous solid.

¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.12–2.25 (1H, m), 4.02 (1H, d,J=6.6 Hz), 4.87 (2H, d, J=3.2 Hz), 4.97 (2H, s), 6.55 (1H, d, J=2.2 Hz),7.01 (1H, dd, J=1.3, 3.5 Hz), 7.08–7.14 (2H, m) 7.28–7.39 (5H, m) 7.43(1H, dd, J=1.3, 5.3, Hz), 7.68–7.80 (4H, m), 8.36 (1H, d, J=9.2 Hz).

(6) To a suspension of2-{[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione(1.37 g, 2.5 mmol) in ethanol (20 ml) was added hydrazine monohydrate(0.36 ml, 7.5 mmol). The mixture was refluxed for 1 h. The reactionmixture was poured into a saturated sodium hydrogencarbonate solutionand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (20 ml), and thendi-t-butyl dicarbonate (0.69 ml, 3 mmol) was added thereto. Theresulting mixture was refluxed for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting crystals were recrystallized from ethylacetate-diisopropyl ether to givetert-butyl[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(1.19 g, 92.2%) as crystals.

Melting point 176–177° C. Elemental analysis for C₃₀H₃₄N₂O₄S Calculated:C, 69.47; H, 6.61; N, 5.40. Found: C, 69.44; H, 6.68; N, 5.36.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.14–2.28 (1H,m), 4.05 (2H, bs), 4.30 (2H, d, J=5.0 Hz), 4.56 (1H, bs), 4.98 (2H, s),6.55 (1H, d, J=2.6 Hz), 6.94 (1H, dd; J=1.2, 3.5 Hz), 7.10 (1H, dd,J=2.6, 8.8 Hz), 7.17 (1H, dd, J=3.5, 5.4 Hz), 7.26–7.39 (5H, m), 7.48(1H, dd, J=1.2, 5.4 Hz), 8.35 (1H, d, J=8.8 Hz).

(7)Tert-butyl[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressure,and the precipitated crystals were recrystallized from ethylacetate-diisopropyl ether to give3-(aminomethyl)-6-(benzyloxy)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinonehydrochloride (0.11 g, 84.6%) as crystals.

Melting point 139–141° C. Elemental analysis for C₂₅H₂₇N₂O₂ClS 0.5H₂OCalculated: C, 64.71; H, 6.08; N, 6.04. Found: C, 65.01; H, 6.18; N,5.74. ¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.99–2.09 (1H, m),3.98; (2H, bs), 4.08 (2H, bs), 5.06 (2H,bs), 6.49 (1H, d, J=2.2 Hz),7.20–7.41(8H, m), 7.85 (1H, dd, J=1.1, 5.1 Hz), 8.23 (1H, d, J=9.0 Hz),8.59 (3H, bs).

Example 2543-(Aminomethyl)-6-hydroxy-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinonehydrochloride

(1) A suspension oftert-butyl[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(1.04 g, 2 mmol) and 5% palladium carbon (1.0 g) in ethanol (10 ml) andtetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere at roomtemperature for 2 h. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to givetert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.82 g, 96.5%) as crystals.

Melting point 216–217° C. Elemental analysis for C₂₃H₂₈N₂O₄S Calculated:C, 64.46; H, 6.59; N, 6.54. Found: C, 64.38; H, 6.60; N, 6.33.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.13–2.25 (1H,m), 4.04 (2H, bs), 4.30 (2H, d, J=5.2 Hz), 4.57 (1H, bs), 6.53 (1H, d,J=2.4 Hz), 6.97 (1H, d, J=2.8 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.13(1H, dd, J=2.8, 5.6 Hz), 7.40 (1H, bs), 7.42 (1H, d, J=5.6 Hz), 8.28(1H, d, J=8.8 Hz).

(2)Tert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.15 g, 0.35 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate solution (5 ml.) The solution was stirred at roomtemperature for 2 h. The reaction mixture was concentrated under reducepressure, and the residue was crystallized from ethylacetate-diisopropyl ether to give3-(aminomethyl)-6-hydroxy-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinonehydrochloride (0.10 g, 83.3%) as crystals.

Melting point 249–251° C. Elemental analysis for C₁₈H₂₁N₂O₂ClS H₂OCalculated: C, 56.46; H, 6.05; N, 7.32. Found: C, 56.54; H, 6.35; N,7.06. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.99–2.12 (1H, m), 3.98(2H, bs), 4.08 (2H, bs), 6.41 (1H, d, J=2.3 Hz), 7.03 (1H, dd, J=2.3,8.6 Hz), 7.06 (1H, bs), 7.26–7.29 (2H, m), 7.82 (1H, dd, J=2.8, 3.8 Hz),8.14 (1H, d, J=8.6 Hz), 8.67 (3H, bs).

Example 2552-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinyl]oxy}acetamidehydrochloride

(1) A solution oftert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.43 g, 1 mmol), and 2-iodoacetamide (0.37 g, 2 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.30 ml, 2 mmol) inN,N-dimethylacetamide (10 ml) was stirred at 80° C. for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.19 g, 39.6%) as crystals.

Melting point 219–221° C. Elemental analysis for C₂₅H₃₁N₃O₅S 0.25H₂OCalculated: C, 61.27; H, 6.48; N, 8.57. Found: C, 61.02; H, 6.38; N,8.37. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.16–2.26(1H, m), 4.07 (2H, bs), 4.31 (2H, d, J=6.0 Hz), 4.39 (2H, s), 4.61 (1H,bs), 5.72 (1H, bs), 6.50 (1H, d, J=2.5 Hz), 6.51 (1H, bs), 7.01 (1H, dd,J=1.2, 3.6 Hz), 7.06 (1H, dd, J=2.5, 8.9 Hz), 7.20 (1H, dd, J=3.6, 5.4Hz), 7.51 (1H, dd, J=1.2, 5.4 Hz), 8.40 (1H, d, J=8.9 Hz).

(2)Tert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.14 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 2 h. The reaction was concentrated under reduced pressure to give2-{[3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinyl]oxy}acetamidehydrochloride (0.11 g, 91.7%) as an amorphous solid.

¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.99–2.14 (1H, m), 3.98–4.09(4H, m), 4.41 (2H, s), 6.50 (1H, d, J=2.6 Hz), 7.21 (1H, dd, J=2.6, 9.0Hz), 7.26–7.30 (2H, m), 7.35 (1H, bs), 7.60 (1H, bs), 7.83 (1H, dd,J=2.6, 4.0 Hz), 8.26 (1H, d, J=9.0 Hz), 8.63 (3H, s).

Example 256 Methyl3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride

(1) To a solution oftert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(1.07 g, 2.5 mmol) in N,N-dimethylformamide (10 ml) was added sodiumhydride (0.12 g, 3 mmol) (60% in oil) at 0° C., and then the mixture wasstirred at 0° C. for 30 min. To the mixture was addedN-phenyltrifluoromethanesulfonimide (1.07 g, 3 mmol), and the resultingmixture was stirred at room temperature for 2 h. The reaction mixturewas poured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to givetert-butyl[2-isobutyl-1-oxo-4-(2-thienyl)-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(1.40 g, 100%) as an oil.

¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.44 (9H, s), 2.15–2.27 (1H,m), 4.11 (2H, bs), 4.35 (2H, d, J=5.2 Hz), 4.58 (1H, bs), 7.00–7.06 (2H,m), 7.20–7.45 (2H, m), 7.53 (1H, dd, J=1.2, 5.3 Hz), 8.52 (1H, d, J=8.4Hz).

(2) A mixture oftert-butyl[2-isobutyl-1-oxo-4-(2-thienyl)-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate(1.40 g, 2.5 mmol), 1,1′-bis(diphenylphosphino)ferrocene (66 mg, 0.12mmol), triethylamine (0.39 ml, 2.8 mmol) and palladium acetate (27 mg,0.12 mmol) in tetrahydrofuran (20 ml) and methanol (20 ml) was stirredat 100° C. under a carbon monoxide atmosphere at 5 atom for 3 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give methyl3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylate(1.02 g, 87.2%) as crystals.

Melting point 170–171° C. Elemental analysis for C₂₅H₃₀N₂O₅S Calculated:C, 63.81; H, 6.43; N, 5.95. Found: C, 63.68; H, 6.68; N, 5.68.¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=7.0 Hz), 1.44 (9H, s), 2.17–2.31 (1H,m), 3.88 (3H, s), 4.10 (2H, d, J=7.4 Hz), 4.34 (2H, d, J=5.8 Hz), 4.64(1H, bs) 7.05 (1H, dd, J=1.1, 3.4 Hz), 7.21 (1H, dd, J=3.4, 5.2 Hz),7.52 (1H, dd, J=1.1, 5.2 Hz), 7.82 (1H, d, J=1.3 Hz), 8.04 (1H, dd,J=1.3, 8.4 Hz), 8.48 (1H, dd, J=0.8, 8.4 Hz).

(3) Methyl3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylate(0.14 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 2 h. The reaction mixture was concentrated under reduced pressure,and the residue was crystallized from ethyl acetate-diisopropyl ether togive methyl3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylatehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 227–229° C. Elemental analysis for C₂₀H₂₃N₂O₃ClS 0.25H₂OCalculated: C, 58.39; H, 5.76; N, 6.81. Found: C, 58.28; H, 6.09; N,6.41. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 1.99–2.18 (1H, m), 3.35(2H, s), 3.84 (3H, s), 4.03 (2H, bs), 7.29–7.33 (2H, m), 7.72 (1H, d,J=1.4 Hz), 7.88 (1H, dd, J=2.6, 4.0 Hz), 8.08 (1H, dd, J=1.4, 8.4 Hz),8.44 (1H, d, J=8.4 Hz), 8.69 (3H, bs).

Example 2573-(Aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylicacid hydrochloride

(1) To a solution of methyl3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylate(0.85 g, 1.8 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) wasadded 1N sodium hydroxide solution (4 ml). The resulting mixture wasstirred at room temperature for 1 h. The reaction mixture was pouredinto water, acidified with 1N hydrochloric acid and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingcrystals were recrystallized from tetrahydrofuran-diisopropyl ether togive3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylicacid (0.79 g, 96.3%) as crystals.

Melting point 224–226° C. Elemental analysis for C₂₄H₂₈N₂O₅S Calculated:C, 63.14; H, 6.18; N, 6.14. Found: C, 63.00; H, 6.04; N, 5.94.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.49 (9H, s), 2.12–2.26 (1H,m), 4.05 (2H, d, J=6.4 Hz), 4.30 (2H, d, J=4.4 Hz), 5.61 (1H, bs), 7.09(1H, d, J=3.5 Hz), 7.21 (1H, dd, J=3.5, 5.2 Hz), 7.53 (1H, dd, J=0.9,5.2 Hz), 7.65 (1H, s), 7.91 (1H, d, J=8.6 Hz), 8.36 (1H, d, J=8.6 Hz).

(2)3-{[(Tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylicacid (0.14 g, 0.3 mmol) was dissolved in a solution of 4N hydrogenchloride in ethyl acetate (5 ml). The solution was stirred at roomtemperature for 1 h. The reaction mixture was concentrated under reducedpressure, and the residue was crystallized from ethylacetate-diisopropyl ether to give3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylicacid hydrochloride (0.10 g, 90.9%) as crystals.

Melting point 208–210° C. Elemental analysis for C₁₉H₂₁N₂O₃ClS H₂OCalculated: C, 55.54; H, 5.64; N, 6.82. Found: C, 55.37; H, 5.74; N,6.60. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.8 Hz), 1.99–2.19 (1H, m), 3.33(2H, s), 4.04 (2H, s), 7.28–7.32 (2H, m), 7.72 (1H, d, J=1.4 Hz),7.86–7.89 (1H, m), 8.06 (1H, dd, J=1.7, 8.2 Hz), 8.41 (1H, d, J=8.2 Hz),8.60 (3H, bs).

Example 2583-(Aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxamidehydrochloride

(1) A solution of3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylicacid (0.59 g, 1.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.50 g, 2.6 mmol) and 1-hydroxybenzotriazole ammoniumsalt (0.40 g, 2.6 mmol) in N,N-dimethylformamide (10 ml) was stirred atroom temperature for 2 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting crystals were recrystallized fromtetrahydrofuran-diisopropyl ether to givetert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.56 g, 94.9%) as crystals.

Melting point 248–250° C. Elemental analysis for C₂₄H₂₉N₃O₄S Calculated:C, 63.27; H, 6.42; N, 9.22. Found: C, 62.99; H, 6.62; N, 9.00.¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 1.46 (9H, s), 2.14–2.27(1H, m),4.08 (2H, d, J=7.4 Hz), 4.31 (2H, d, J=5.4 Hz), 5.01 (1H, bs), 6.23 (2H,bs), 7.06 (1H, d, J=2.6 Hz), 7.17 (1H, dd, J=2.6, 5.2 Hz), 7.48 (1H, d,J=5.2 Hz), 7.52 (1H, d, J=1.7 Hz), 7.73 (1H, dd, J=1.7, 8.4 Hz), 8.38(1H, d, J=8.4 Hz).

(2)Tert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.23 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure, and theprecipitated crystals were crystallized from methanol-diethyl ether togive3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxamidehydrochloride (0.18 g, 94.7%) as crystals.

Melting point 246–248° C. Elemental analysis for Cl₁₉H₂₂N₃O₃ClS 0.75H₂OCalculated: C, 56.29; H, 5.84; N, 10.36. Found: C, 56.19; H, 5.97; N,10.22. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 2.02–2.18 (1H, m),3.43 (2H, bs), 4.02 (2H, bs), 7.29–7.33 (2H, m), 7.61–7.63 (2H, m),7.84–7.87 (1H, m), 8.01 (1H, dd, J=1.5, 8.4 Hz), 8.19 (1H, bs), 8.35(1H, d, J=8.4 Hz), 8.60 (3H, bs).

Example 2593-(Aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarbonitrilehydrochloride

(1) A solution oftert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.23 g, 0.5 mmol) and cyanuric chloride (0.28 g, 1.5 mmol) inN,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[6-cyano-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.20 g, 95.2%) as crystals.

Melting point 189–190° C. Elemental analysis for C₂₄H₂₇N₃O₃S Calculated:C, 65.88; H, 6.22; N, 9.60. Found: C, 65.96; H, 6.14; N, 9.51.¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.44 (9H, s), 2.14–2.31 (1H,m), 4.10 (2H, bs), 4.36 (2H, bs), 4.57 (1H, bs), 7.03 (1H, dd, J=1.2,3.6 Hz), 7.23 (1H, dd, J=3.6, 5.1 Hz), 7.46 (1H, d, J=1.5 Hz), 7.55 (1H,dd, J=1.2, 5.1 Hz), 7.65 (1H, dd, J=1.5, 8.2 Hz), 8.52 (1H, d, J=8.2Hz).

(2)Tert-butyl[6-cyano-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.17 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure, and theresidue was crystallized from ethyl acetate diisopropyl ether to give3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarbonitrilehydrochloride (0.14 g, 93.3%) as crystals.

Melting point 202–203° C. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz),2.06–2.16 (1H, m), 3.98–4.09 (4H, m), 7.29–7.33 (2H, m), 7.41 (1H, s),7.87–7.91 (1H, m), 7.98 (1H, dd, J=1.1, 8.4 Hz), 8.46 (1H, d, J=8.4 Hz),8.69 (3H, bs).

Example 2603-(Aminomethyl)-4-butoxy-2-isobutyl-6-(2-pyridyl)-1(2H)-isoquinolinonedihydrochloride

(1) A solution oftert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.48 g, 1 mmol), tri-n-butyl(2-pyridyl)tin (0.37 g, 1 mmol) andtetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) inN,N-dimethylformamide (10 ml) was stirred at 100° C. for 10 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to givetert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-pyridyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.36 g, 75.0%) as crystals.

Melting point 123–124° C. Elemental analysis for C₂₈H₃₇N₃O₄ Calculated:C, 70.12; H, 7.78; N, 8.76. Found: C, 69.91; H, 8.07; N, 8.71.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.05 (3H, t, J=7.3 Hz), 1.47(9H, s), 1.53–1.72 (2H, m), 1.84–1.97 (2H, m), 2.05–2.27 (1H, m), 3.94(2H, t, J=6.4 Hz), 4.01 (2H, d, J=7.8 Hz), 4.55 (2H, d, J=5.4 Hz), 4.82(1H, bs), 7.28–7.37 (1H, m), 7.77–7.85 (2H, m), 8.13 (1H, dd, J=1.8, 8.4Hz), 8.32 (1H, d, J=1.8 Hz), 8.50 (1H, d, J=8.4 Hz), 8.74–8.78 (1H, m).

(2)Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-pyridyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.31 g, 0.65 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 2 h. The reaction was concentrated under reduced pressure to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-(2-pyridyl)-1(2H)-isoquinolinonedihydrochloride (0.27 g, 93.1%) as an amorphous solid.

Elemental analysis for C₂₃H₃₁N₃O₂Cl₂ H₂O Calculated: C, 58.72; H, 7.07;N, 8.93. Found: C, 59.20; H, 7.46; N, 8.91. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H,d, J=6.3 Hz), 1.01 (3H, t, J=7.2 Hz), 1.56–1.64 (2H, m), 1.87–1.95 (2H,m), 1.99–2.18 (1H, m), 4.02–4.06 (4H, m), 4.23 (2H, bs), 7.73 (1H, bs),8.27–8.28 (3H, m), 8.42–8.44 (2H, m), 8.46 (4H, bs).

Example 2613-(Aminomethyl)-4-butoxy-2-isobutyl-6-(2-thienyl)-1(2H)-isoquinolinonehydrochloride

(1) A solution oftert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.48 g, 1 mmol), tri-n-butyl(2-thienyl)tin (0.32 ml, 1 mmol) andtetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) intetrahydrofuran (20 ml) was refluxed for 12 h. The reaction mixture waspoured into water and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to givetert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.22 g, 45.8%) as crystals.

Melting point 130–131° C. Elemental analysis for C₂₇H₃₆N₂O₄S Calculated:C, 66.91; H, 7.49; N, 5.78. Found: C, 66.85; H, 7.56; N, 5.70.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 1.06 (3H, t, J=7.3 Hz), 1.47(9H, s), 1.55–1.73 (2H, m), 1.83–1.97 (2H, m), 2.05–2.25 (1H, m), 3.91(2H, t, J=6.4 Hz), 3.99 (2H, d, J=7.4 Hz), 4.53 (2H, d, J=5.6 Hz), 4.75(1H, bs), 7.15 (1H, dd, J=3.6, 5.2 Hz), 7.39 (1H, dd, J=1.1, 5.2 Hz),7.48 (1H, dd, J=1.1, 3.6 Hz), 7.75 (1H, dd, J=1.6, 8.4 Hz), 7.90 (1H, d,J=1.6 Hz), 8.40 (1H, d, J=8.4 Hz).

(2)Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 2 h. The reaction was concentrated under reduced pressure, and theresulting crystals were recrystallized from methanol-diisopropyl etherto give3-(aminomethyl)-4-butoxy-2-isobutyl-6-(2-thienyl)-1(2H)-isoquinolinonehydrochloride (0.11 g, 91.7%) as crystals.

Melting point 167–170° C. ¹H-NMR(DMSO-d₆), δ: 0.89 (6H, d, J=6.6 Hz),1.03 (3H, t, J=7.3 Hz), 1.56–1.73 (2H, m), 1.82–2.11 (3H, m), 3.95–4.01(4H, m), 4.20 (2H, s), 7.24 (1H, dd, J=3.7, 5.1 Hz), 7.72–7.76 (2H, m),7.90 (1H, d, J=1.6 Hz), 7.96 (1H, dd, J=1.66, 8.4 Hz), 8.30 (1H, d,J=8.4 Hz), 8.64 (3H, bs).

Example 2623-(Aminomethyl)-4-butoxy-6-(2-furyl)-2-isobutyl-1(2H)-isoquinolinonehydrochloride

(1) A solution oftert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.48 g, 1 mmol), tri-n-butyl(2-furyl)tin (0.31 ml, 1 mmol) andtetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) intetrahydrofuran (20 ml) was refluxed at 80° C. for 12 h. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography to givetert-butyl[4-butoxy-6-(2-furyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.35 g, 76.1%) as crystals.

Melting point 157–158° C. Elemental analysis for C₂₇H₃₆N₂O₅ Calculated:C, 69.21; H, 7.74; N, 5.98. Found: C, 68.88; H, 7.98; N, 5.75.¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 1.06 (3H, t, J=7.3 Hz), 1.47(9H, s), 1.57–1.70 (2H, m), 1.86–1.95 (2H, m), 2.14–2.23 (1H, m), 3.91(2H, t, J=6.6 Hz), 3.99 (2H, d, J=7.2 Hz), 4.53 (2H, d, J=5.7 Hz), 4.78(1H, bs), 6.54 (1H, dd, J=1.5, 3.3 Hz), 6.85 (1H, dd, J=0.6, 3.3 Hz),7.56 (1H, dd, J=0.6, 1.5 Hz), 7.76 (1H, dd, J=1.5, 8.4 Hz), 7.97 (1H, d,J=1.5 Hz), 8.40 (1H, d, J=8.4 Hz).

(2)Tert-butyl[4-butoxy-6-(2-furyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.28 g, 0.6 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 2 h. The reaction was concentrated under reduced pressure, and theresidue was crystallized from ethyl acetate-diisopropyl ether to give3-(aminomethyl)-4-butoxy-6-(2-furyl)-2-isobutyl-1(2H)-isoquinolinonehydrochloride (0.22 g, 91.7%) as crystals.

Melting point 189–191° C. Elemental analysis for C₂₂H₂₉N₂O₃Cl 1.75H₂OCalculated: C, 60.54; H, 7.51; N, 6.42. Found: C, 60.46; H, 7.07; N,6.33. ¹H-NMR(DMSO-d₆) δ: 0.88 (6H, d, J=6.6 Hz), 1.02 (3H, t, J=7.3 Hz),1.51–1.69 (2H, m), 1.81–2.08 (3H, m), 3.93–3.99 (4H, m), 4.18 (2H, d,J=4.8 Hz), 6.99 (1H, dd, J=1.8, 3.3 Hz), 7.23 (1H, d, J=3.3 Hz),7.90–7.97 (3H, m), 8.28 (1H, d, J=8.8 Hz), 8.75 (3H, bs).

Example 2633-(Aminomethyl)-4-butoxy-2-isobutyl-6-phenyl-1(2H)-isoquinolinonehydrochloride

(1) A mixture oftert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.48 g, 1 mmol), phenylboric acid (0.15 g, 1.2 mmol), sodium carbonate(0.26 g, 2.5 mmol), toluene (10 ml), ethanol (2 ml) and water (2 ml) wasstirred at room temperature under an argon atmosphere for 30 min. To theresulting mixture was added tetrakis(triphenylphosphine)palladium (58mg, 0.05 mmol), and then the mixture was refluxed under an argonatmosphere for 10 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto givetert-butyl(4-butoxy-2-isobutyl-1-oxo-6-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.42 g, 89.4%) as crystals.

Melting point 155–159° C. Elemental analysis for C₂₉H₃₈N₂O₄ Calculated:C, 72.77; H, 8.00; N, 5.85. Found: C, 72.52; H, 7.81; N, 5.73.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.03 (3H, t, J=7.3 Hz), 1.47(9H, s), 1.48–1.69 (2H, m), 1.81–1.95 (2H, m), 2.13–2.26 (1H, m), 3.92(2H, t, J=6.6 Hz), 4.02 (2H, d, J=7.4 Hz), 4.55 (2H, d, J=5.4 Hz), 4.78(1H, bs), 7.39–7.56 (3H, m), 7.66–7.75 (3H, m), 7.89 (1H, d, J=1.4 Hz),8.49 (1H, d, J=8.6 Hz).

(2)Tert-butyl(4-butoxy-2-isobutyl-1-oxo-6-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.34 g, 0.7 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure, and theresidue was crystallized from methanol-diisopropyl ether to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-phenyl-1(2H)-isoquinolinonehydrochloride (0.28 g, 96.6%) as crystals.

Melting point 180–181° C. Elemental analysis for C₂₄H₃₁N₂O₂ClCalculated: C, 69.46; H, 7.53; N, 6.75. Found: C, 69.15; H, 7.70; N,6.81. ¹H-NMR(DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.00 (3H, t, J=7.4 Hz),1.51–1.69 (2H, m), 1.80–2.12 (3H, m), 3.90–4.05 (4H, m), 4.22 (2H, s),7.45–7.62 (3H, m), 7.77–7.82 (2H, m), 7.91–7.95 (2H, m), 8.37 (1H, d,J=8.8 Hz), 8.71 (3H, bs).

Example 2643-(Aminomethyl)-4-butoxy-2-isobutyl-6-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1(2H)-isoquinolinonehydrochloride

(1) A mixture of triphenyl(1,3-thiazol-4-ylmethyl)phosphonium chloride(0.44 g, 1.1 mmol), potassium carbonate (15 g, 1.1 mmol) andtert-butyl(4-butoxy-6-formyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.47 g, 1.1 mol) in N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 10 h. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting crystals were recrystallized from ethylacetate-diisopropyl ether to givetert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.46 g, 80.7%) as crystals.

Melting point 141–142° C. Elemental analysis for C₂₉H₃₇N₃O₄S 0.55H₂OCalculated: C, 65.39; H, 7.19; N, 7.89. Found: C, 65.58; H, 7.33; N,8.11. ¹H-NMR(CDCl₃) δ: 0.97 (6H, d, J=7.0 Hz), 1.06 (3H, t, J=7.3 Hz),1.47 (9H, s), 1.48–1.69 (2H, m), 1.83–1.97 (2H, m), 2.11–2.25 (1H, m),3.89 (2H, t, J=6.6 Hz), 3.99 (2H, d, J=7.4 Hz), 4.52 (2H, d, J=5.4 Hz),4.77 (1H, bs), 7.31 (1H, d, J=16.0 Hz), 7.32 (1H, d, J=16.0 Hz), 7.32(1H, d, J=1.8 Hz), 7.62–7.74 (3H, m), 8.39 (1H, d, J=8.8 Hz), 8.87 (1H,d, J=1.4 Hz).

(2)Tert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloridein ethyl acetate solution (5 ml). The solution was stirred at roomtemperature for 1 h. The reaction was concentrated under reducedpressure, and the residue was recrystallized from methanol-diisopropylether to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-[(E)-2-(1,3-thiazol-4-yl-)ethenyl]-1(2H)-isoquinolinonehydrochloride (0.11 g, 84.6%) as crystals.

Melting point 164–166° C. Elemental analysis for C₂₄H₃₀N₃O₂ClS 0.75H₂OCalculated: C, 56.52; H, 6.42; N, 8.24. Found: C, 56.44; H, 6.41; N,8.21. ¹H-NMR(DMSO-d₆) δ: 0.89 (6H, d, J=6.6 Hz), 1.06 (3H, t, J=7.1 Hz),1.50–1.68 (2H, m), 1.83–2.10 (3H, m), 3.91–4.00 (4H, m), 4.18 (2H, d,J=4.4 Hz), 7.56 (1H, d, J=16.2 Hz), 7.67 (1H, d, J=16.2 Hz), 7.84 (1H,s), 7.87 (1H, d, J=1.8 Hz), 7.94 (1H, dd, J=1.8, 8.6 Hz), 8.26 (1H, d,J=8.6 Hz), 8.69 (3H, bs), 9.22 (1H, s).

Example 2653-(Aminomethyl)-4-butoxy-2-isobutyl-6-[2-(1,3-thiazol-4-yl)ethyl]-1(2H)-isoquinolinonehydrochloride

(1) A suspension oftert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.21 g, 0.4 mmol) and 5% palladium carbon (0.2 g) in tetrahydrofuran(10 ml) was stirred under a hydrogen atmosphere at room temperature for2 h. The catalyst was filtered off, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to givetert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[2-(1,3-thiazol-4-yl)ethyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.20 g, 95.2%) as crystals.

Melting point 103–104° C. Elemental analysis for C₂₉H₃₉N₂C₄S 0.5H₂OCalculated: C, 65.14; H, 7.54; N, 7.86. Found: C, 65.34; H, 7.53; N,8.12. ¹H-NMR(CDCl₃) δ: 0.95 (6H, d, J=7.0 Hz), 1.04 (3H, t, J=7.3 Hz),1.46 (9H, s), 1.46–1.65 (2H, m), 1.77–1.91 (2H, m), 2.09–2.24 (1H, m),3.22 (4H, s) 3.79 (2H, t, J=6.6 Hz), 3.89 (2H, d, J=7.2 Hz), 4.50 (2H,d, J=5.6 Hz), 4.70 (1H, bs), 6.86 (1H, d, J=2.0 Hz), 7.33 (1H, dd,J=1.6, 8.2 Hz), 7.44 (1H, d, J=1.6 Hz), 8.33 (1H, d, J=8.2 Hz), 8.78(1H, d, J=2.0 Hz).

(2)Tert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[2-(1,3thiazol-4-yl)ethyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.16 g, 0.3 mmol) was dissolved in absolution of 4N hydrogen chloridein ethyl acetate (5 ml). The solution was stirred at room temperaturefor 1 h. The reaction was concentrated under reduced pressure to give3-(aminomethyl)-4-butoxy-2-isobutyl-6-[2-(1,3-thiazol-4-yl)ethyl]-1(2H)-isoquinolinonehydrochloride (0.13 g, 92.9%) as an amorphous solid.

Elemental analysis for C₂₄H₃₂N₃O₂ClS 2.5H₂O Calculated: C, 56.85; H,7.35; N, 8.29. Found: C, 56.80; H, 7.20; N, 8.13. ¹H-NMR(DMSO-d₆) δ:0.87 (6H, d, J=6.6 Hz), 1.00 (3H, t, J=7.3 Hz), 1.48–1.67 (2H, m),1.77–1.87 (2H, m), 1.96–2.05 (1H, m), 3.16–3.21 (4H, m), 3.84 (2H, t,J=6.3 Hz), 3.94 (2H, d, J=6.0 Hz), 4.15 (2H, d, J=5.1 Hz), 7.35–7.38(1H, m), 7.49–7.51 (2H, m), 8.18 (1H, d, J=8.7 Hz), 8.56 (3H, bs),9.11–9.18 (1H, m).

Example 2666-Amino-3-(aminomethyl)-2–4-butoxy-2neopentyl-1(2H)-isoquinolinonedihydrochloride

(1) 9H-Fluoren-9-ylmethyl4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinylcarbamate(1.14 g, 87.7%) as an amorphous solid. [synthesized according to themethod similar to that in Example 82(1) from4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylicacid (0.92 g, 2 mmol)]

¹H-NMR(CDCl₃); δ: 0.99 (9H, s), 1.01 (3H, t, J=7.4 Hz), 1.44 (9H, s),1.45–1.62 (2H, m), 1.79–1.90 (2H, m), 3.86 (2H, t, J=6.4 Hz), 4.10 (2H,bs), 4.29 (1H, t, J=6.4 Hz), 4.54–4.62 (4H, m), 4.72 (1H, bs), 7.10 (1H,bs), 7.26–7.46 (5H, m), 7.63 (2H, d, J=7.3 Hz), 7.79 (2H, d, J=7.3 Hz),8.78 (1H, s), 8.32 (1H, d, J=8.8 Hz).

(2)Tert-butyl(6-amino-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.66 g, 90.4%) as an amorphous solid. [synthesized according to themethod similar to that in Example 82(2) from 9H-fluoren-9-ylmethyl4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinylcarbamate(1.11 g, 1.7 mmol)]

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.02 (3H, t, J=7.4 Hz), 1.44 (9H, s),1.50–1.60 (2H, m), 1.70–1.88 (2H, m), 3.83 (2H, t, J=6.5 Hz), 4.19 (2H,bs), 4.53 (2H, d, J=5.4 Hz), 4.67 (1H, bs), 6.78–6.81 (2H, m), 8.20 (1H,d, J=9.0 Hz).

(3) 6-amino-3-(aminomethyl)-4-butoxy-2-neopentyl-1(2H)-isoquinolinonedihydrochloride (0.19 g, 95.0%) as an amorphous solid. [synthesizedaccording to the method similar to that in Example 82(3) fromtert-butyl(6-amino-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.21 g, 0.5 mmol)]

Elemental analysis for C₁₉H₃₁N₃O₂Cl₂ Calculated: C, 56.43; H, 7.73; N,10.39. Found: C, 56.71; H, 8.05; N, 10.00. ¹H-NMR(DMSO-d₆) δ: 0.88 (9H,s), 1.02. (3H, t, J=6.2 Hz), 1.48–1.59 (2H, m), 1.77–1.91 (2H, m), 3.88(2H, t, J=5.9 Hz); 4.00 (2H, bs), 4.19 (2H, bs), 6.53 (3H, bs),6.98–7.04 (2H, m), 8.03 (1H, d, J=8.4 Hz), 8.54 (3H, bs).

Example 267N-[3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]acetamidehydrochloride

(1)Tert-butyl[6-(acetylamino)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.30 g, 63.8%) as crystals. [synthesized according to the methodsimilar to that in Example 88(1) fromtert-butyl(6-amino-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.43 g, 1 mmol)]

Melting point 120–121° C. ¹NMR(CDCl₃) δ: 0.99 (9H, s), 1.01 (3H, t,J=7.0 Hz), 1.45 (9H, s), 1.4–1.66 (2H, m), 1.79–1.93 (2H, m), 2.26 (3H,s), 3.88 (2H, t, J=6.6 Hz) 4.14 (2H, bs), 4.56 (2H, d, J=5.6 Hz), 4.86(1H, bs), 7.34 (1H, d, J8.6 Hz), 7.88 (1H, bs), 8.15 (1H, s), 8.28 (1H,d, J=8.6 Hz).

(2)N-[3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]acetamide(0.19 g, 95.0%) as crystals. [synthesized according to the methodsimilar, to that in Example 88(2) fromtert-butyl[6-(acetylamino)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.24 g, 0.5 mmol)]

Melting point 191–193° C. Elemental analysis for C₂₁H₃₂N₃O₃Cl 0.5H₂OCalculated: C, 60.20; H, 7.94; N, 10.03. Found: C, 60.43; H, 8.07; N,9.90. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 0.99 (3H, t, J=6.2 Hz), 1.43–1.67(2H, m), 1.72–1.93 (2H, m), 2.13 (3H, s), 3.92 (2H, s), 4.05 (2H, bs),4.22 (2H, s), 7.70 (1H, d, J=8.6 Hz), 8.08 (1H, d, J=8.6 Hz), 8.27 (1H,s), 8.52 (3H, bs), 10.63 (1H, s).

Example 2683-(Aminomethyl)-7-(benzyloxy)-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride.

(1) Ethyl7-(benzyloxy)-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(24.01 g, 91.0%) as crystals. [synthesized according to the methodsimilar to that in Example 154(2) from ethyl7-(benzyloxy)-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate(19.77 g, 50 mmol)]¹H-NMR(CDCl₃) δ: 0.90 (6H, d, J=6.6 Hz), 1.44 (3H, t,J=7.1 Hz), 1.96–2.07 (1H, m), 4.12 (2H, d, J=7.2 Hz), 4.45 (2H, q, J=7.1Hz), 5.21 (2H, s), 7.30–7.48 (6H, m), 7.74 (1H, d, J=9.0 Hz); 7.96 (1H,d, J=9.0 Hz).

(2) Ethyl7-(benzyloxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate(16.21 g, 79.1%) as crystals. [synthesized according to the methodsimilar to that in Example 154(3) from ethyl7-(benzyloxy)-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate(23.74 g, 45 mmol) and phenylboronic acid (6.58 g, 54 mmol)]

Melting point 107–108° C. Elemental analysis for C₂₉H₂₉NO₄ Calculated:C, 76.46; H, 6.42; N, 3.07. Found: C, 76.45; H, 6.54; N, 3.06.¹H-NMR(CDCl₃) δ: 0.87 (3H, d, J=7.2 Hz), 0.94 (6H, d, J=6.6 Hz),2.05–2.23 (1H, m), 3.93 (2H, q, J=7.2 Hz), 4.05 (2H, d, J=7.4 Hz), 5.21(2H, s), 7.13–7.50 (12H, m), 8.03 (1H, d, J=2.2 Hz).

(3)7-(Benzyloxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylicacid (11.21 g, 74.9%) as an amorphous; solid. [synthesized according tothe method similar to that in Example 154(4) from ethyl7-(benzyloxy)-2-isobutyl-1oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate(15.94 g, 35 mmol)]

¹H-NMR(CDCl₃) δ: 0.90 (6H, d, J=6.8 Hz), 2.14–2.28 (1H, m), 4.01 (2H, d,J=7.8 Hz), 5.15 (2H, s), 7.11–7.48 (12H, m), 7.66 (1H, d, J=1.8 Hz).

(4)7-(Benzyloxy)-3-(hydroxymethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(9.31 g, 90.1%) as crystals. [synthesized according to the methodsimilar to that in Example 154(5) from7-(benzyloxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylicacid (10.69 g, 25 mmol)]

Melting point 125–126° C. Elemental analysis for C₂₇H₂₇NO₃ 0.5H₂OCalculated: C, 76.75; H, 6.68; N, 3.32. Found: C, 76.36; H, 6.46; N,3.24. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=7.0 Hz), 2.05 (1H, bs), 2.20–2.34(1H, m), 4.25 (2H, d, J=7.2 Hz), 4.46 (2H, d, J=3.6 Hz), 5.11 (2H, s),6.92 (1H, d, J=8.8 Hz), 7.11 (1H, dd, J=2.6, 8.8 Hz), 7.29–7.56 (10H,m), 7.91 (1H, d, J=2.6 Hz).

(5)7-(Benzyloxy)-3-(chloromethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(7.44 g, 86.2%) as an oil. [synthesized according to the method similarto that in Example 154(6) from7-(benzyloxy)-3-(hydroxymethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(8.27 g, 20 mmol)]

¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=7.0 Hz), 2.16–2.31 (1H, m), 4.20 (2H, d,J=7.4 Hz), 4.42 (2H, s), 5.20 (2H, s), 6.96 (1H, d, J=8.8 Hz,) 7.13–7.54(11H, m), 8.01 (1H, d, J=2.8 Hz).

(6)2-{[7-(Benzyloxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinolinyl]methyl}-1H-isoindolone-1,3(2H)-dione(8.74 g, 94.8%) as an amorphous solid. [synthesized according to themethod similar to that in Example 154(7) from7-(benzyloxy)-3-(chloromethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone(7.34 g, 17 mmol)]

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 2.17–2.31 (1H, m), 4.08 (2H, d,J=7.0 Hz), 4.78 (2H, s), 5.19 (2H, s), 6.92 (1H, d, J=9.0 Hz), 7.17 (1H,dd, J=2.8, 9.0 Hz), 7.21–7.49 (10H, m), 7.66–7.78 (4H, m), 7.98 (1H, d,J=2.8 Hz).

(7)Tert-butyl[7-(benzyloxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(7.56 g, 92.2%) as crystals. [synthesized according to the methodsimilar to that in Example 154(8) from2-{[7-(benzyloxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindolone-1,3(2H)-dione(8.68 g, 16 mmol)]

Melting point 181–182° C. Elemental analysis for C₃₂H₃₆N₂O₄ Calculated:C, 74.97; H, 7.08; N, 5.46. Found: C, 74.94; H, 7.14; N, 5.31.¹H-NNR(CDCl₃) δ: 1.0 (6H, d, J=6.8 Hz), 1.43 (9H, s), 2.20–2.31 (1H, m),4.08 (2H, d, J=7.4 Hz), 4.19 ((2H, d, J=5.2 Hz), 4.55 (1H, bs), 5.16(2H, s), 6.89 (1H, d, J=8.8 Hz), 7.15 (1H, dd, J=2.8, 8.8 Hz), 7.24–7.55(10H, m), 7.96 (1H, d, J=2.88 Hz).

(8)3-(Aminomethyl)-7-(benzyloxy)-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride (0.21 g, 95.5%) as crystals. [synthesized according to themethod similar to that in Example 214(3) fromtert-butyl[-7-(benzyloxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.26 g, 0.5 mmol)]

Melting point 242–243° C. Elemental analysis for C₂₇H₂₉N₂O₂ClCalculated: C, 72.23; H, 6.51; N, 6.24. Pound: C, 71.99; H, 6.54; N,6.05. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 1.99–2.19 (1H, m), 3.85(2H, d, J=4.8 Hz), 4.09 (2H, s), 5.26 (2H, s), 6.85 (1H, d, J=8.8 Hz),7.33–7.57 (11H, m), 7.85 (1H, d, J=2.6 Hz), 8.58 (3H, bs).

Example 2693-(Aminomethyl)-7-hydroxy-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl(7-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(5.75 g, 97.3%) as crystals. [synthesized according to the methodsimilar to that in Example 154(9) fromtert-butyl[7-(benzyloxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(7.14 g, 14 mmol)]

Melting point 232–233° C. Elemental analysis for C₂₅H₃₀N₂O₄ Calculated:C, 71.07; H, 7.16; N, 6.63. Found: C, 70.81; H, 7.22; N, 6.35.¹H-NMR(CDCl₃) δ: 1.02 (6H, d, J=7.0 Hz), 1.42 (9H, s), 2.21–2.35 (1H,m), 4.11 (2H, d, J=7.2 Hz), 4.22 (2H, d, J=5.2 Hz), 4.52 (1H, bs), 6.91(1H, d, J=8.8 Hz), 7.16 (1H, dd, J=2.6, 8.8 Hz), 7.23–7.28 (2H, m),7.44–7.55 (3H, m), 8.52 (1H, d, J=2.8 Hz), 8.90 (1H, s).

(2) 3-(Aminomethyl)-7-hydroxy-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride (0.17 g, 94.4%) as crystals. [synthesized according to themethod similar to that in Example 214(3) fromtert-butyl(7-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.21 g, 0.5 mmol)]

Melting point 259–261° C. Elemental analysis for C₂₀H₂₃N₂O₂Cl 0.25H₂OCalculated: C, 66.11; H, 6.52; N, 7.71. Found: C, 66.00; H, 6.51; N,7.53. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 2.00–2.16 (1H, m), 3.85(2H, s), 4.05 (2H, d, J=7.0 Hz), 6.76 (1H, d, J=8.8 Hz), 7.13 (1H, dd,J=2.8, 8.8 Hz), 7.35–7.39 (2H, m), 7.47–7.60 (2H, m), 7.68 (1H, d, J=2.8Hz), 8.48 (3H, bs), 10.27 (1H, bs).

Example 2703-(Aminomethyl)-7-ethoxy-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl(7-ethoxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.39 g, 86.7%) as crystals. [synthesized according to the methodsimilar to that in Example 154(10) fromtert-butyl(7-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.42 g, 1 mmol) and 2-iodoethane (0.12 ml, 1.5 mmol)]

Melting point 163–164° C. Elemental analysis for C₂₇H₃₄N₂O₄ Calculated:C, 71.97; H, 7.61; N, 6.22. Found: C, 71.67; H, 7.41; N, 6.28.¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.42 (9H, s), 1.44 (3H, t,J=7.4 Hz), 2.19–2.35 (1H, m), 4.06–4.21 (6H, m) 4.48 (1H, bs), 6.88 (1H,d, J=9.0 Hz), 7.09 (1H, dd, J=2.7, 9.0 Hz), 7.23–7.27 (2H, m), 7.46–7.53(3H, m), 7.86 (1H, d, J=2.6 Hz).

(2) 3-(Aminomethyl)-7-ethoxy-2-isobutyl-4-phenyl-1(2H)-isoquinolinonehydrochloride (0.18 g, 66.7%) as crystals. [synthesized according to themethod similar to that in Example 214(3) fromtert-butyl(7-ethoxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.32 g, 0.07 mmol)]

Melting point 154–155° C. Elemental analysis for C₂₂H₂₇N₂O₂Cl 0.25H₂OCalculated: C, 67.51; H, 7.08; N, 7.16. Found: C, 67.30; H, 7.04; N,7.10. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 1.37 (3H, t, J=6.8 Hz),2.01–2.19 (1H, m), 3.86 (2H, s), 4.07–4.20 (4H, m), 6.83 (1H, d, J=9.0Hz), 7.27 (1H, dd, J=2.8, 9.0 Hz), 7.37–7.41 (2H, m), 7.54–7.57 (3H, m),7.73 (1H, d, J=2.8 Hz), 8.53 (3H, s).

Example 2713-(Aminomethyl)-2-isobutyl-7-(2-methoxyethoxy)-4-phenyl-1(2H)-isoquinolinonehydrochloride

(1)Tert-butyl[2-isobutyl-7-(2-methoxyethoxy)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.34 g, 70.8%) as crystals. [synthesized according to the methodsimilar to that in Example 154(10) fromtert-butyl(7-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.42 g, 1 mmol) and bromoethyl methyl ether (0.14 ml, 1.5 mmol)]

Melting point 124–125° C. Elemental analysis for C₂₈H₃₆N₂O₅ Calculated:C, 69.98; H, 7.55; N, 5.83. Found: C, 69.81; H, 7.37; N, 5.96.¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.19–2.35 (1H,m), 3.45 (3H, s), 3.74–3.80 (2H, m), 4.08 (2H, d, J=7.0 Hz), 4.19–4.27(4H, m), 4.51 (1H, bs), 6.89 (1H, d, J=8.6 Hz), 7.16 (1H, dd, J=2.8, 8.6Hz), 7.19–7.27 (2H, m), 7.47–7.52 (3H, m), 7.86 (1H, d, J=2.8 Hz).

(2)3-(Aminomethyl)-2-isobutyl-7-(2-methoxyethoxy)-4-phenyl-1(2H)-isoquinolinonehydrochloride (0.21 g, 84.0%) as crystals. [synthesized according to themethod similar to that in Example 214(3) fromtert-butyl[2-isobutyl-7-(2-methoxyethoxy)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.28 g, 0.6 mmol)]

Melting point 148–149° C. Elemental analysis for C₂₃H₂₉N₂O₃Cl 0.5H₂OCalculated: C, 64.85; H, 7.10; N, 6.58. Found: C, 65.25; H, 7.21; N,6.73. ¹H-NMR(DMSO-d₆) δ: 0.92 (6H, d, J=6.2 Hz), 1.99–2.21 (1H, m), 3.31(3H, s), 3.63–3.69 (2H, m), 3,86 (2H, s), 4.07–4.10 (2H, m), 4.22 (2H,s), 6.84 (1H, d, J=9.2 Hz), 7.28–7.40 (3H, m), 7.54–7.62 (3H, m), 7.74(1H, s), 8.56 (3H, s).

Example 2722-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-7-isoquinolinyl]oxy}acetamidehydrochloride

(1)Tert-butyl[7-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.19 g, 40.4%) as crystals. [synthesized according to the methodsimilar to that in Example 154(10) fromtert-butyl(7-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.42 g, 1 mmol) and 2-iodoacetamide (0.27 g, 1.5 mmol)]

Melting point 211–212° C. Elemental analysis for C₂₇H₃₃N₃O₅ Calculated:C, 67.62; H, 6.94; N, 8.76. Found: C, 67.38; H, 6.69; N, 8.87.¹H-NMR(CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.18–2.34 (1H,m), 4.08 (2H, d, J=7.4 Hz), 4.20 (2H, d, J=5.4 Hz), 4.51 (1H, bs), 4.58(2H, s), 5.86 (1H, bs), 6.57 (1H, bs), 6.94 (1H, d, J=8.8 Hz), 7.13 (1H,d, J=8.8 Hz), 7.23–7.27 (2H, m), 7.49–7.52 (3H, m), 7.90 (1H, s).

(2)2-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-7-isoqulinolinyl]oxy}acetamidehydrochloride (0.11 g, 91.2%) as crystals. [synthesized according to themethod similar to that in Example 214(3) fromtert-butyl[7-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.14 g, 0.3 mmol)] Melting point 244–245° C.

Elemental analysis for C₂₂H₂₆N₃O₃Cl 1.75H₂O Calculated: C, 59.06; H,6.65; N, 9.39. Found: C, 59.21; H, 6.52.; N, 9.33. ¹H-NMR(DMSO-d₆) δ:0.92 (6H, d, J=6.6 Hz), 1.99–2.19 (1H, m), 3.85 (2H, d, J=4.2 Hz), 4.09(2H, d, J=7.0 Hz), 4.58 (2H, s), 6.85 (1H, d, J=8.8 Hz), 7.33 (1H, dd,J=2.6, 8.8 Hz), 7.36–7.41 (2H, m), 7.56–7.60 (3H, m), 7.69 (1H, bs),7.72 (1H, d, J=2.6 Hz), 8.64 (3H, s).

Example 2733-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-7-isoquinolinecarboxamidehydrochloride

(1)Tert-butyl(2-isobutyl-1-oxo-4-phenyl-7-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl)methylcarbamate(5.01 g, 90.4%) as an amorphous solid. [synthesized according to themethod similar to that in Example 155(1) fromtert-butyl(7-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(4.22 g, 10 mmol)]

¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.20–2.29 (1H,m), 4.09 (2H, d, J=7.5 Hz), 4.23 (2H, d, J=5.4 Hz), 4.46 (1H, bs), 7.06(1H, d, J=9.0 Hz), 7.22–7.27 (2H, m), 7.36 (1H, dd, J=2.7, 9.0 Hz),7.42–7.56 (3H, m), 8.34 (1H, d, J=2.7 Hz).

(2) Methyl3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-7-isoquinolinecarboxylate(3.11 g, 74.4%) as crystals. [synthesized according to the methodsimilar to that in Example 155(2) fromtert-butyl(2-isobutyl-1-oxo-4-phenyl-7-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl)methylcarbamate(4.99 g, 9 mmol)]

Melting point 134–135° C. Elemental analysis for C₂₇H₃₂N₂O₅ Calculated:C, 69.81; H, 6.94; N, 6.03. Found: C, 69.46; H, 7.04; N, 5.81.¹H-NMR(CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.05–2.28 (1H,m), 3.93 (3H, s), 4.10 (2H, d, J=7.5 Hz), 4.22 (2H, d, J=5.4 Hz), 4.61(1H, bs), 6.98 (1H, d, J=8.7 Hz), 7.24–7.28 (2H, m), 7.46–7.57 (3H, m),8.02 (1H, dd, J=1.8, 8.7 Hz), 9.10 (1H, d, J=1.8 Hz).

(3)3-{[(Tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-7-isoquinolinecarboxylicacid (2.49 g, 92.2%) as crystals. [synthesized according to the methodsimilar to that in Example 155(3) from methyl3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-7-isoquinolinecarboxylate(2.79 g, 6 mmol)]

Melting point 246° C. Elemental analysis for C₂₆H₃₀N₂O₅ 0.25H₂OCalculated: C, 68.62; H, 6.76; N, 6.16. Found: C, 68.88; H, 6.83; N,5.87. ¹H-NMR(CDCl₃) δ: 0.91 (6H, d, J=6.6 Hz), 1.38 (9H, s), 2.12–2.26(1H, m), 3.91 (2H, d, J=6.6 Hz), 3.99 (2H, d, J=4.2 Hz), 6.99 (1H, d,J=8.8 Hz), 7.34 (1H, bs), 7.39–7.42 (2H, m), 7.46–7.56 (3H, m), 8.09(1H, dd, J=2.0, 8.8 Hz), 8.87 (1H, d, J=2.0 Hz).

(4)Tert-butyl[7-(aminocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.86 g, 95.6%) as crystals. [synthesized according to the methodsimilar to that in Example 155(4) from3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-7-isoquinolinecarboxylicacid (0.90 g, 2 mmol)]

Melting point 232–233° C. Elemental analysis for C₂₆H₃₁N₃O₄ 0.5H₂OCalculated: C, 68.10; H, 7.03; N, 9.16. Found: C, 68.31; H, 7.07; N,8.75. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.10–2.24(1H, m), 4.08 (2H, d, J=7.0 Hz), 4.22 (2H, d, J=5.2 Hz), 4.76 (1H, bs),5.96 (1H, bs), 6.74 (1H, bs), 7.02 (1H, d, J=8.6 Hz), 7.25–7.30 (2H, m),7.45–7.56 (3H, m), 8.05 (1H, dd, J=1.4, 8.6 Hz), 8.78 (1H, d, J=1.4 Hz).

(5)3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-7-isoquinolinecarboxamidehydrochloride (0.18 g, 94.7%) as crystals. [synthesized according to themethod similar to that in Example 155(5) fromtert-butyl[7-(aminocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.23 g, 0.5 mmol)]

Melting point 254–256° C. Elemental analysis for C₂₁H₂₄N₃O₂Cl H₂OCalculated: C, 63.87; H, 6.38; N, 10.64. Found: C, 63.76; H, 6.29; N,10.30. ¹H-NMR(DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.04–2.19 (1H, m),3.89 (2H, d, J=34.4 Hz), 4.13 (2H, d, J=7.0 Hz), 6.94 (1H, d, J=8.6 Hz),7.37–7.44 (2H, m), 7.54–7.64 (4H, m), 8.16 (1H, dd, J=1.8, 8.6 Hz), 8.30(1H, bs), 8.67 (3H, bs), 8.85 (1H, d, J=1.8 Hz).

Example 2743-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]propanamidehydrochloride

(1) A suspension of ethyl(E)-3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-2-propenoate(0.90 g, 1.8 mmol) and 5% palladium carbon (0.5 g) in ethanol (10 ml)and tetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere atroom temperature for 2 h. The catalyst was filtered off, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give ethyl3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)propanoate(0.82 g, 90.1%) as an amorphous solid. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d,J=6.6 Hz), 1.19 (3H, t, J=7.1 Hz), 1.42 (9H, s), 2.18–2.29 (1H, m), 2.51(2H, t, J=7.8 Hz), 2.90 (2H, t, J=7.8 Hz), 4.01–4.12 (4H, m), 4.19 (2H,d, J=5.6 Hz), 4.40 (1H, bs), 6.74 (1H, d, J=1.6 Hz), 7.21–7.26 (2H, m),7.31 (1H, dd, J=1.6, 8.4 Hz), 7.46–7.53 (3H, m), 8.39 (1H, d, J=8.4 Hz).

(2) To a solution of ethyl3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)propanoate(0.61 g, 1.2 mmol) in tetrahydrofuran (5 ml) and ethanol (5 ml) wasadded 1N sodium hydroxide solution (3 ml). The resulting mixture wasstirred at room temperature for 1 h. The reaction mixture was pouredinto water, acidified with 1N hydrochloric acid and extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingcrystals were recrystallized from ethyl acetate-diisopropyl ether togive3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)propanoicacid (0.52 g, 91.2%) as crystals.

Melting point 182–183° C. Elemental analysis for C₂₈H₃₄N₂O₅ Calculated:C, 70.12; H, 7.36; N, 5.84. Found: C, 70.21; H, 7.55; N, 5.68.¹H-NMR(CDCl₃) δ: 0.98 (6H, d, J=6.9 Hz), 1.42 (9H, s), 2.15–2.27 (1H,m), 2.58 (2H, t, J=7.8 Hz), 2.91 (2H, t, J=7.8 Hz), 4.06 (2H, d, J=6.0Hz), 4.19 (2H, d, J=5.2 Hz), 4.53 (1H, bs), 6.76 (1H, s), 7.22–7.25 (2H,m), 7.31 (1H, d, J=8.8 Hz), 7.46–7.52 (3H, m), 8.37 (1H, d, J=8.8 Hz).

(3) A solution of3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)propanoicacid (0.33 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammoniumsalt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 ml) was stirred atroom temperature for 2 h. The resulting reaction mixture was poured intowater and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to givetert-butyl[6-(3-amino-3-oxopropyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.31 g, 93.9%) as crystals.

Melting point 239–240° C. Elemental analysis for C₂₈H₃₅N₃O₄ 0.25H₂OCalculated: C, 69.76; H, 7.42; N, 8.72. Found: C, 69.54; H, 7.41; N,8.58. ¹H-NMR(CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.13–2.29(1H, m), 2.43 (2H, t, J=8.0 Hz), 2.92 (2H, t, J=8.0 Hz), 4.05 (2H, d,J=7.4 Hz), 4.19 (2H, d, J=5.2 Hz), 4.54 (1H, bs), 5.42 (2H, bs), 6.75(1H, d, J=1.4 Hz), 7.21–7.30 (3H, m), 7.21–7.30 (3H, m), 7.46–7.57 (3H,m), 8.33–8.37 (1H, m).

(4)3-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]propanamidehydrochloride (0.20 g, 95.3%) as crystals. [synthesized according to themethod similar to that in Example 214(3) fromtert-butyl[6-(3-amino-3-oxopropyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.24 g, 0.5 mmol)]

Melting point 186–187° C. ¹H-NMR(DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz),2.02–2.16 (1H, m), 2.26 (2H, t, J=7.2 Hz), 2.76 (2H, t, J=7.2 Hz), 3.86(2H, s), 4.08 (2H, s), 6.72 (1H, s), 6.75 (1H, bs), 7.29 (1H, bs),7.38–7.40 (2H, m), 7.45 (1H, d, J=8.4 Hz), 7.55–7.59 (3H, m), 8.25 (1H,d, J=8.4 Hz), 8.57 (3H, bs).

Example 2752-(2-{[3-(Aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy}ethyl)-1H-isoindolone-1,3(2H)-dionehydrochloride

To a solution oftert-butyl(4-butoxy-6-hydroxy-2-isobutyl-1-oxo-4-1,2-dihydro-3-isoquinolinyl)methylcarbamate(2.09 g, 5 mmol), N-(2-hydroxyethyl)phthalimide (1.15 g, 6 mmol) andtri-n-butylphosphine (2.5 ml, 10 mmol) in tetrahydrofuran (30 ml) wasadded 1,1′-(azodicarbonyl)dipiperidine (2.52 g, 10 mmol), and themixture was stirred at room temperature for 6 h. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography. The resulting crystals were dissolvedin a solution of 4N hydrogen chloride in ethyl acetate (5 ml). Thesolution was stirred at room temperature for 2 h. The reaction mixturewas concentrated under reduced pressure, and the residue wascrystallized from methanol-diisopropyl ether to give2-(2-{[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy}ethyl)-1H-isoindolone-1,3(2H)-dionehydrochloride (0.14 g, 93.3%) as crystals.

Melting point 176–177° C. ¹H-NMR(DMSO-d₆) δ: 0.86 (6H, d, J=6.6 Hz),0.99 (3H, t, J=7.3 Hz), 1.46–1.64 (2H, m), 1.77–2.06 (3H, m), 3.88–3.94(4H, m), 4.04 (2H, t, J=5.5 Hz), 4.15 (2H, s), 4.41 (2H, t, J=5.5 Hz),7.05 (1H, d, J=2.4 Hz), 7.14 (1H, dd, J=2.4, 9.0 Hz) 7.82–7.92 (4H, m),8.15 (1H, d, J=9.0 Hz), 8.53 (3H, bs).

Example 2763-[3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]propanamidehydrochloride

(1) Ethyl3-(3-{[(tert-butoxycarbonyl)amino]methyl}-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl)propanoate(0.68 g, 88.3%) as an oil. [synthesized according to the method similarto that in Example 274(1) from ethyl(E)-3-(3-{[(tert-butoxycarbonyl)amino]methyl}-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-2-propenoate(0.77 g, 1.5 mmol)]

¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t, J=7.2 Hz), 1.24 (3H, t,J=7.0 Hz), 1.45 (9H, s), 1.49–1.68 (2H, m), 1.80–1.94 (2H, m), 2.70 (2H,t, J=7.8 Hz), 3.11 (2H, t, J=7.8 Hz), 3.86 (2H, t, J=6.6 Hz), 4.10 (2H,bs), 4.14 (2H, q, J=7.0 Hz), 4.58 (2H, s), 4.62 (1H, bs), 7.35 (1H, dd,J=1.6, 8.2 Hz), 7.51 (1H, d, J=1.6 Hz), 8.33 (1H, d, J=8.4 Hz),

(2)3-(3-{[(Tert-butoxycarbonyl)amino]methyl}-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl)propanoicacid (0.40 g, 90.9%) as crystals. [synthesized according to the methodsimilar to that in Example 274(2) from ethyl3-(3-{[(tert-butoxycarbonyl)amino]methyl}-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl)propanoate(0.46 g, 0.9 mmol)]

¹H-NMR(CDCl₃) δ: 0.98 (9H, s), 1.03 (3H, t, J=7.4 Hz), 1.45 (9H, s),1.46–1.67 (2H, m), 1.79–1.92 (2H, m), 2.77 (2H, t, J=7.4 Hz), 3.11 (2H,t, J=7.4 Hz), 3.84 (2H, t, J=6.4 Hz), 4.14 (2H, bs), 4.57 (2H, d, J=5Hz), 4.75 (1H, bs), 7.34 (1H, dd, J=1.6, 8.5 Hz), 7.52 (1H, d, J=1.6Hz), 8.32 (1H, d, J=8.5 Hz).

(3)Tert-butyl[6-(3-amino-3-oxopropyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.19 g, 86.4%) as crystals. [synthesized according to the methodsimilar to that in Example 274(3) from3-(3-{[(tert-butoxycarbonyl)amino]methyl}-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl)propanoicacid (0.22 g, 0.45 mmol)]

Melting point 87–88° C. Elemental analysis for C₂₇H₄₁N₃O₅ Calculated: C,66.50; H,8.47; N, 8.62. Found: C, 66.25; H, 8.35; N, 8.54. ¹H-NMR(CDCl₃)δ: 0.99 (9H, s), 1.04 (3H, t, J=7.4 Hz), 1.45 (9H, s), 1.52–1.72 (2H,m), 1.80–1.94 (2H, m), 2.60 (2H, t, J=7.7 Hz), 3.13 (2H, t, J=7.7 Hz),3.86 (2H, t, J=6.6 Hz), 4.14 (2H, bs), 4.56 (2H, d, J=5.4 Hz), 4.73 (1H,bs), 5.50 (2H, bs), 7.32 (1H, d, J=8.2 Hz), 7.52 (1H, s), 8.29 (1H, d,J=8.2 Hz).

(4)3-[3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]propanamidehydrochloride (0.11 g, 91.7%) as crystals. [synthesized according to themethod similar to that in Example 274(4) from tert-butyl[6-(3-amino-3-oxopropyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.14 g, 0.3 mmol)]

Melting point 151–153° C. Elemental analysis for C₂₇H₄₁N₃O₅ClCalculated: C, 66.50; H, 8.47; N, 8.62. Found: C, 66.25; H, 8.35; N,8.54. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.3 Hz), 1.51–1.62(2H, m), 1.78–1.91 (2H, m), 2.46 (2H, t, J=7.4 Hz), 3.00 (2H, t, J=7.4Hz), 3.93 (2H, t, J=6.1 Hz), 4.08 (2H, bs), 4.23 (2H, d, J=4.0 Hz), 6.82(1H, bs), 7.44 (1H, bs), 7.47 (1H, d, J=8.2 Hz), 7.58 (1H, s), 8.17 (1H,d, J=8.2 Hz), 8.53 (3H, bs).

Example 277[3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]acetonitrilehydrochloride

(1) To a solution of p-toluenesulfonylmetyl isocyanide (0.94 g, 4.8mmol) in 1,2-dimethoxyethane (20 ml) were added potassium t-butoxide(0.90 g, 8 mmol) andtert-butyl(4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate(1.78 g, 4 mmol) at −70° C., and the mixture was stirred at −70° C. for1 h. To the mixture was added methanol (30 ml), and the mixture wasrefluxed for 30 min. The reaction mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto givetert-butyl[4-butoxy-6-(cyanomethyl)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.66 g, 36.3%) as an amorphous solid.

¹H-NMR(CDCl₃) δ: 1.00 (9H, s), 1.04 (3H, t, J=7.4 Hz), 1.45 (9H, s),1.51–1.66 (2H, m), 1.82–1.92 (2H, m), 3.88 (2H, t, J=6.2 Hz); 3.92 (2H,s), 4.18 (2H, bs), 4.58 (2H, d, J=5.0 Hz), 4.72 (1H, bs), 7.40 (1H, dd,J=1.8, 8.4 Hz), 7.70 (1H, d, J=1.18 Hz), 8.40 (1H, d, J=8.4 Hz).

(2)[3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]acetonitrilehydrochloride (0.10 g, 90.9%) as crystals. [synthesized according to themethod similar to that in Example 214(3) fromtert-butyl[4-butoxy-6-(cyanomethyl)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.14 g, 0.3 mmol)].

Melting point 169–171° C. Elemental analysis for C₂₁H₃₀N₃O₂Cl 0.25H₂OCalculated: C, 63.62; H, 7.73; N, 10.60. Found: C, 63.70; H, 7.85; N,10.59. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t, J=7.4 Hz),1.52–1.63 (2H, m), 1.80–1.91 (2H, m), 3.94 (2H, t, J=6.6 Hz), 4.14 (2H,bs), 4.26 (2H, bs), 4.33 (2H, s), 7.57 (1H, dd, J=1.4, 8.0 Hz), 7.78(1H, d, J=1.4 Hz), 8.29 (1H, d, J=8.0 Hz), 8.54 (3H, bs).

Example 2782-[3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]acetamidehydrochloride

(1) To a solution oftert-butyl[4-butoxy-6-(cyanomethyl)-2-neopentyl-1oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.45 g, 1 mmol) in ethanol (20 ml) was added a solution of potassiumhydroxide (0.40 g, 10 mmol) in water (5 ml). The mixture was refluxedfor 10 h. The reaction mixture was poured into water, acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give crude amorphous solid. Asolution of the amorphous solid,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g, 1mmol) and 1-hydroxybenzotriazole ammonium salt (0.15 g, 1 mol) inN,N-dimethylformamide (10 ml) was stirred for 2 h at room temperature.The resulting reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel to givetert-butyl[6-(2-amino-2-oxoethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate.(0.13 g, 54.2%) as crystals.

Melting point 197–198° C. ¹H-NMR(CDCl₃) δ: 0.99 (9H, s), 1.04 (3H, t,J=7.4 Hz), 1.45 (9H, s), 1.46–1.64 (2H, m), 1.80–1.90 (2H, m), 3.74 (2H,s), 3.87 (2H, t, J=6.5 Hz), 4.14 (2H, bs), 4.57 (2H, d, J=5.4 Hz), 4.71(1H, bs), 5.47 (1H, bs), 5.54 (1H, bs), 7.40 (1H, dd, J=1.4, 8.0 Hz),7.60 (1H, d, J=1.4 Hz), 8.38 (1H, d, J=8.0 Hz).

(2)Tert-butyl[6-(2-amino-2-oxoethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate(95 mg, 0.2 mmol) was dissolved in a solution of 4N hydrogen chloride inethyl acetate (5 ml). The solution was stirred at room temperature for 2h. The reaction was concentrated under reduced pressure, and the residuewas crystallized from methanol-diisopropyl ether to give2-[3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]acetamidehydrochloride (75 mg, 91.5%) as crystals.

Melting point 163–165° C. ¹H-NMR(DMSO-d₆) δ: 0.90 (9H, s), 1.00 (3H, t,J=7.5 Hz), 1.52–1.59 (2H, m) 1.80–1.90 (2H, m), 3.61 (2H, s), 3.93 (2H,s), 4.02 (2H, bs), 4.24 (2H, s), 7.03 (1H, bs), 7.50 (1H, d, J=8.5 Hz),7.67 (1H, s), 7.69 (1H, bs), 8.20 (1H, d, J=8.5 Hz).

Example 279[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]acetonitrilehydrochloride

(1) To a mixture oftert-butyl[6-(hydroxymethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.33 g, 0.75 mmol), triethylamine (0.18 mL, 1.1 mmol),N,N,N′,N′-tetramethyletylenediamine (0.011 mL, 0.075 mmol), toluene (6mL) and tetrahydrofuran (6 mL) was added dropwise a solution ofmethanesulfonyl chloride (0.088 mL, 1.1 mmol) in toluene, (4 mL) underice-cooling. The mixture was stirred under ice-cooling for 30 min, thereaction mixture was poured into 0.1N hydrochloric acid (50 mL) andextracted with ethyl acetate (50 mL). The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to give(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)methylmethanesulfonate (0.39 g, 100%) as colorless powder.

¹H-NMR (CDCl₃) δ: 1.01 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.15–2.30 (1H,m), 2.91 (3H, s), 4.09 (2H, d, J=7.0 Hz), 4.22 (2H, d, J=6.0 Hz), 4.45(1H, br), 5.18 (2H, s), 6.93 (1H, d, J=1.0 Hz), 7.15–7.30 (2H, m),7.45–7.60 (4H, m), 8.51 (1H, d, J=8.6 Hz).

(2) To a mixture of(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)methylmethanesulfonate (39 g, 0.75 mmol) in acetonitrile (5 mL) andtetrahydrofuran (4 mL) were added trimethylsilyl cyanide (0.15 mL, 1.1mmol) and a solution of 1.0 M tetrabutylammonium fluoride: intetrahydrofuran (1.1 mL), and then the mixture was stirred at 80° C. for30 min. The reaction mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=5:2 (v/v)) to givetert-butyl[6-(cyanomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.25 g, 75%) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.01 (6H, d, J=6.8 Hz), 1.43 (9H, s), 2.15–2.30 (1H,m), 3.71 (2H, s), 4.09 (2H, d, J=6.8 Hz), 4.21 (2H, d, J=5.4 Hz), 4.46(1H, br), 6.86 (1H, d, J=1.8 Hz), 7.20–7.30(2H, m), 7.43 (1H, dd, J=1.8,8.4 Hz), 7.50–7.60 (3H, m), 8.49 (1H, d, J=8.4 Hz).

(3) To a solution oftert-butyl[6-(cyanomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.13 g, 0.29 mmol) in ethyl acetate (4 mL) was added a 4N hydrogenchloride ethyl acetate solution (1 mL), and the mixture was stirred atroom temperature for 12 h. The reaction was concentrated under reducedpressure, and the residue was crystallized from diisopropyl ether andwashed with diisopropyl ether (5 mL×2) to give[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]acetonitrilehydrochloride (0.096 g, 88%) as a pale yellow powder.

¹H-NMR (DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 1.95–2.20 (1H, m), 3.87 (2H,bs), 4.06 (2H, d, J=5.4 Hz), 4.13 (2H, s), 6.85–6.95 (1H, m), 7.35–7.45(3H, m), 7.50–7.65 (3H, m), 8.36 (1H, d, J=8.0 Hz), 8.43 (3H, bs).

Melting point: 142–144° C.

Example 280N-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-N′-methoxyureahydrochloride

(1) To solution of3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carboxylicacid (0.15 g, 0.33 mmol) in N,N-dimethylformamide (5 mL) was addeddiphenylphosphoryl azide (0.09 mL, 0.40 mmol) and triethylamine (0.056mL, 0.40 mmol), and the mixture was stirred at room temperature for 2 h.The reaction mixture was poured into water (50 mL) and extracted withethyl acetate (30 mL×2). The organic layers were combined, washed withwater (50 mL) and brine (20 mL), dried, over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was dissolved intoluene (20 mL), and the solution was refluxed for 1 h. The reactionmixture was allowed to cool to room temperature, and a mixture ofO-methylhydroxyamine hydrochloride (0.088 g, 0.40 mmol) andtriethylamine (0.056 mL, 0.40 mmol) in N,N-dimethylformamide (2 mL) wasadded thereto. The resulting reaction mixture was stirred at roomtemperature for 1 h and then poured into water (100 mL). The organiclayer was separated and the aqueous layer was extracted twice with ethylacetate. The organic layers were combined, washed with 0.1M aqueouscitric acid solution (20 mL) and brine (10 mL), dried over anhydrous,magnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=1:1 (v/v)) to givetert-butyl(2-isobutyl-6-{[(methoxyamino)carbonyl]amino}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.13 g, 81%) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.9 Hz), 1.43 (9H, s), 2.20–2.35 (1H,m), 3.74 (3H, d, J=0.6 Hz), 4.05 (2H, d, J=6.9 Hz), 4.19 (2H, d, J=5.5Hz), 4.59 (1H, br), 6.95 (1H, bs), 7.22 (1H, br), 7.25–7.30 (3H, m),7.45–7.70 (4H, m), 8.40 (1H, d, J=8.7 Hz).

(2)N-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-N′-methoxyureahydrochloride (0.049 g, 46%) as a pale yellow powder[synthesizedaccording to the method similar to that in Example 279

(3) fromtert-butyl(2-isobutyl-6-{[(methoxyamino)carbonyl]amino}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.12 g, 0.25 mmol)]

¹H-NMR (DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 2.00–2.20 (1H, m), 3.55 (3H,s), 3.83 (2H, bs), 4.02 (2H, d, J=6.6 Hz), 7.25 (1H, d, J=1.8 Hz),7.30–7.40 (2H, m), 7.50–7.60 (3H, m), 7.82 (1H, dd, J=1.8, 8.8 Hz), 8.21(1H, d, J=8.8 Hz), 8.39 (3H, bs), 9.29 (1H, s), 9.60 (1H, s). Meltingpoint: 297–299° C.

Example 2813-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarbohydrazidedihydrochloride

(1) A mixture of methyl3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carboxylate(0.12 g, 0.27 mmol) and hydrazine monohydrate (0.65 mL, 13 mmol) inmethanol (6 mL) was stirred in a sealed tube at 75° C. for 2 h. Thereaction mixture was concentrated, and the residue was recrystallizedfrom water-methanol to givetert-butyl[6-(hydrazinocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)]methylcarbamate(0.12 g, 96%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=7.0 Hz), 1.43 (9H, s), 2.20–2.30 (1H,m), 2.48 (3H, br), 4.08 (2H, d, J=7.0 Hz), 4.20 (2H, d, J=5.2 Hz), 4.70(1H, br), 7.20–7.30 (3H, m), 7.45–7.55 (3H, m), 7.69 (1H, d, J=5.4 Hz),8.43 (1H, d, J=8.6 Hz).

(2)3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarbohydrazidedihydrochloride (0.095 g, 95%) as a pale yellow powder. [synthesizedaccording to the method similar to that in Example 279 (3) fromtert-butyl[6-(hydrazinocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.11 g, 0.29 mmol)]

¹H-NMR (DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.00–2.20 (1H, m), 3.88 (2H,bs), 4.09 (2H, d, J=7.0 Hz), 7.35–7.45 (3H, m), 7.55–7.65 (3H, m), 8.00(1H, dm, J=8.4 Hz), 8.45 (H, d, J=8.4 Hz), 8.56 (3H, bs), 11.62 (1H,bs). Melting point 291–292° C.

Example 2823-(Aminomethyl)-2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-phenyl-1(2H)-isoquinolinone

(1) A mixture oftert-butyl[6-(hydrazinocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.23 g, 0.50 mmol) and trimethyl orthoacetate (2.0 mL, 11 mmol) in1-butanol (10 mL) was refluxed for 20 min. To the reaction mixture wasadded 1,8-diazabicyclo[5.4.0]-7-undecene (0.075 mL, 0.50 mmol), and thenthe mixture was refluxed for 1 h. The resulting reaction mixture wasneutralized with acetic acid (0.040 mL, 0.70 mmol) and concentratedunder reduced pressure. The residue was partitioned between water (10mL) and ethyl acetate (30 mL). The organic layer was washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1 (v/v)) to givetert-butyl[2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.22 g, 91%) as crystals.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=7.2 Hz), 1.43 (9H, s), 2.15–2.35 (1H,m), 2.57 (3H, s), 4.10 (2H, d, J=7.2 Hz), 4.22 (2H, d, J=5.4 Hz), 4.57(1H, br), 7.20–7.35 (2H, m), 7.50–7.65 (4H, m), 8.05 (1H, dm, J=8.4 Hz),8.58 (1H, dd, J=1.4, 8.4 Hz).

(2) A mixture oftert-butyl[2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.20 g, 0.41 mmol) and 4N hydrogen chloride ethyl acetate solution (4mL) was stirred for 17 h at room temperature. The reaction mixture wasconcentrated, the residue was washed with diisopropyl ether (5 mL×2) togive a pale yellow powder. The powder was added to aqueous saturatedsodium hydrogencarbonate (30 mL), the resulting mixture was extractedwith ethyl acetate-tetrahydrofuran (1:1, v/v, 50 mL×2). The organiclayers were combined, washed with brine (25 mL), dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate:methanol=20:1 (v/v)) and recrystallized from n-hexane-ethylacetate to give3-(aminomethyl)-2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-phenyl-1(2H)-isoquinolinone(0.11 g, 72%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 2.15–2.40 (1H, m), 2.57 (3H,s), 3.69 (2H, bs), 4.24 (2H, d, J=7.4 Hz), 7.25–7.35 (2H, m), 7.45–7.60(3H, m), 7.62 (1H, d, J=1.6 Hz), 8.05 (1H, dd, J=1.6, 8.4 Hz), 8.59 (1H,d, J=8.4 Hz). Melting point: 179–181° C.

Example 2832-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]acetamidehydrochloride

(1) A mixture oftert-butyl[6-(cyanomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.13 g, 0.29 mmol), 2N potassium hydroxide solution (5 mL) and ethanol(5 mL) was refluxed for 4 h. The reaction mixture was diluted with 0.1Nsodium hydroxide solution (100 mL) and washed with ethyl acetate (20mL×2). The aqueous layer was separated, acidified with 1N hydrochloricacid and extracted with ethylacetate (100 mL×2). The organic layers werecombined, washed with brine (20 mL), saturated aqueous sodiumhydrogencarbonate (50 mL) and brine (50 mL), dried over, anhydrousmagnesium sulfate and concentrated under reduced pressure to give(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)aceticacid (0.36 g, 87%) as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.15–2.35 (1H,m), 3.60 (2H, s), 3.95–4.25 (4H, m), 4.48 (1H, br), 6.81 (1H, d, J=1.2Hz), 7.10–7.30 (3H, m), 7.38 (1H, d, J=7.5 Hz), 7.45–7.55 (2H, m), 8.40(1H, dm, J=7.5 Hz).

(2) A mixture of(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)aceticacid (0.15 g, 0.32 mmol), 1-hydroxybenzotriazole ammonium salt (0.074 g,0.48 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.093 g, 0.48 mmol) in N,N-dimethylformamide (10 mL) wasstirred at room temperature for 17 h. The reaction mixture was pouredinto 0.1N aqueous citric acid solution (50 mL) and extracted with ethylacetate (25 mL×2). The organic layers were combined, washed with 0.1Naqueous citric acid solution (50 mL), saturated aqueous sodiumhydrogencarbonate (50 mL), and brine (50 mL), dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate) to givetert-butyl[6-(2-amino-2-oxoethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.12 g, 81%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.15–2.30 (1H,m), 3.54 (2H, s), 4.00–4.25 (4H, m), 4.44 (1H, br), 5.31 (2H, br), 6.82(1H, m), 7.20–7.30 (2H, m), 7.35–7.55 (4H, m), 8.46 (1H, dm, J=8.0 Hz).

(3)2-[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]acetamidehydrochloride (0.090 g, 90%) as pale yellow crystals. [synthesizedaccording to the method similar to that in Example 279 (3) fromtert-butyl[6-(2-amino-2-oxoethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.11 g, 0.25 mmol)]

¹H-NMR (CD₃OD) δ: 1.00 (6H, d, J=6.6 Hz), 2.10–2.30 (1H, m), 3.52 (2H,s), 4.05–4.20 (4H, m), 7.00 (1H, d, J=1.2 Hz), 7.35–7.45 (2H, m),7.50–7.65 (5H, m), 8.37 (1H, d, J=8.0 Hz). Melting point: 231–233° C.

Example 2842-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methyl}-1H-isoindolone-1,3(2H)-dionehydrochloride

(1) To a solution of(3-{[(tert-butoxycarbonyl)amino]methyl}-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl)methylmethanesulfonate (1.1 g, 2.11 mmol) in N,N-dimethylformamide (20 mL) wasadded potassium phthalimide (0.47 g, 2.5 mmol), and the mixture wasstirred at room temperature for 17 h. The reaction mixture was pouredinto water (200 mL) and extracted with ethyl acetate (100 mL×2). Theorganic layers were combined, washed with 0.2N hydrochloric acid (100mL), saturated aqueous sodium hydrogencarbonate (50 mL) and brine (50mL), dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=5:2 (v/v)) to givetert-butyl{6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.99 g, 84%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.42 (9H, s), 2.10–2.30 (1H,m), 4.05 (2H, d, J=7.4 Hz), 4.20 (2H, d, J=7.4 Hz), 4.42 (1H, br), 4.80(2H, s), 6.90 (1H, d, J=1.2 Hz), 7.15–7.25 (2H, m), 7.35–7.45 (4H, m),7.65–7.75 (2H, m), 7.75–7.85 (2H, m), 8.40 (1H, d, J=8.0 Hz).

(2)2-{[-3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methyl}-1H-isoindolone-1,3(2H)-dionehydrochloride (0.10 g, 100%) as a colorless powder. [synthesizedaccording to the method similar to that in Example 279 (3) fromtert-butyl{6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.11 g, 0.20 mmol)]

¹H-NMR (DMSO-d₆) δ: 0.90 (6H, d, J=6.6 Hz), 1.95–2.20 (1H, m), 3.87 (2H,bs), 4.04 (2H, d, J=5.4 Hz), 4.77 (2H, s), 6.65–6.75 (1H, m), 7.25–7.30(2H, m), 7.35–7.45 (3H, m), 7.52 (1H, dm, J=8.2 Hz), 7.87 (4H, s), 8.29(1H, d, J=8.2 Hz), 8.31 (3H, bs). Melting point: 196–199° C.

Example 285N-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methyl}acetamidehydrochloride

(1) A mixture oftert-butyl{6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl}methylcarbamate(0.85 g, 1.5 mmol), and hydrazine monohydrate (0.6 mL, 12 mmol) inethanol (20 mL) and tetrahydrofuran (10 mL) was stirred at roomtemperature for 17 h. The reaction mixture was filtered, and thefiltrate was concentrated. After the residue was dissolved in ethylacetate (50 mL), the solution was filtrated to remove insolublematerial. The filtrate was concentrated to givetert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.82 g) as a crude pale yellow oil. To a solution of the crude oil(0.16 g) in tetrahydrofuran (2 mL) was added acetic anhydride (0.034 mL,0.36 mmol), and then the mixture was stirred at room temperature for 4h. The reaction mixture was washed with water (4 mL) and concentrated.The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1 (v/v)) to givetert-butyl{6-[(acetylamino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.090 g, 63%) as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 1.96 (3H, s),2.25–2.35 (1H, m), 4.06 (2H, d, J=7.6 Hz), 4.19 (2H, d, J=5.4 Hz), 4.38(2H, d, J=6.6 Hz), 4.59 (1H, br), 5.84 (1H, br), 6.76 (1H, m), 7.20–7.55(6H, m), 8.38 (1H, dm, J=8.4 Hz).

(2)N-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methyl}acetamidehydrochloride (0.068 g, 96%) as a pale yellow-powder. [synthesizedaccording to the method similar to that in Example 279 (3) fromtert-butyl{6-[(acetylamino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.082 g, 0.17 mmol)]

¹H-NMR (DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.75 (3H, s), 1.95–2.20 (1H,m), 3.87 (2H, bs), 4.04 (2H, d, J=6.6 Hz), 4.20 (2H, d, J=6.6 Hz), 6.73(1H, s), 7:30–7.40 (2H, m), 7.44 (1H, dd, J=1.6, 8.4 Hz), 7.50–7.60 (3H,m), 8.28 (1H, d, J=8.4 Hz), 8.30–8.45 (4H, m). Melting point: 134–139°C.

Example 286N-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methyl}-2-methylpropanamidehydrochloride

(1) To a solution of crudetert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.016 g) (Example 285) in tetrahydrofuran (2 mL) was added isobutyrylchloride (0.038 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol),and the mixture was stirred at room temperature for 4 h. The reactionmixture was washed with water (4 mL) and concentrated. The residue waspurified by silica gel column chromatography (n-hexane:ethyl acetate=4:1(v/v)) to givetert-butyl{2-isobutyl-6-[(isobutyrylamino)methyl]-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.11 g, 75%) as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.07 (6H, d, J=7.0 Hz), 1.43(9H, s), 2.15–2.35 (2H, m), 4.06 (2H, d, J=7.2 Hz), 4.20 (2H, d, J=5.4Hz), 4.41 (2H, d, J=6.2 Hz), 4.58 (1H, br), 5.79 (1H, br), 6.77 (1H, d,J=1.2 Hz), 7.20–7.60 (6H, m), 8.38 (1H, dm, J=8.2 Hz).

(2)N-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methyl}-2-methylpropanamidehydrochloride (0.091 g, 98%) as a pale yellow powder. [synthesizedaccording to the method similar to that in Example 279 (3) fromtert-butyl{2-isobutyl-6-[(isobutyrylamino)methyl]-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.11 g, 0.21 mmol)]

¹H-NMR (DMSO-d₆) δ: 0.86 (6H, d, J=6.6 Hz), 0.91 (6H, d, J=6.6 Hz),1.95–2.35 (2H, m), 3.84 (2H, bs), 4.06 (2H, d, J=7.0 Hz), 4.24 (2H, d,J=5.8 Hz), 6.75 (1H, s), 7.30–7.40 (2H, m), 7.43 (1H, dd, J=1.0, 8.4Hz), 7.45–7.60 (3H, m), 8.27 (1H, bs), 8.27 (1H, d, J=8.4 Hz), 8.52 (3H,bs). Melting point: 189–191° C.

Example 287Ethyl[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methylcarbamatehydrochloride

(1) To a solution of crudetert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.16 g) (Example 285) in tetrahydrofuran (2 mL) were added ethylchloroformate (0.035 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36mmol), and the mixture was stirred at room temperature for 4 h. Thereaction mixture was washed with water (4 mL) and concentrated. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=4:1 (v/v)) to give ethyl(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)methylcarbamate(0.13 g, 87%) as pale yellow powder.

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.21 (3H, t, J=7.0 Hz), 1.42(9H, s), 2.15–2.35 (1H, m), 4.07 (2H, d, J=7.8 Hz), 4.09 (2H, q, J=7.0Hz), 4.19 (2H, d, J=7.4 Hz), 4.31 (2H, d, J=6.6 Hz), 4.49 (1H, br), 4.96(1H, br), 6.79 (1H, s), 7.20–7.55 (6H, m), 8.42 (1H, d, J=8.4 Hz).

(2)Ethyl[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methylcarbamatehydrochloride (0.092 g, 88%) as a colorless powder. [synthesizedaccording to the method similar to that in Example 279 (3) fromethyl(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)methylcarbamate(0.12 g, 0.24 mmol)]

¹H-NMR (DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.11 (3H, t, J=7.4 Hz),2.00–2.20 (1H, m), 3.86 (2H, bs), 3.91 (2H, q, J=7.4 Hz), 4.07 (2H, d,J=7.8 Hz), 4.13 (2H, d, J=6.0 Hz), 6.77 (1H, s), 7.30–7.40 (2H, m), 7.45(1H, dd, J=1.6, 8.2 Hz), 7.50–7.60 (3H, m), 7.64 (1H, d, J=6.0 Hz), 8.28(1H, d, J=8.2 Hz), 8.55 (3H, bs). Melting point: 184–187° C.

Example 288N-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methyl}methanesulfoneamidehydrochloride

(1) To a solution of crudetert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.16 g) (Example 285) in tetrahydrofuran (2 mL) was addedmethanesulfonyl chloride (0.028 mL, 0.36 mmol) and triethylamine (0.050mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h.The reaction mixture was washed with water (4 mL) and concentrated. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=2:1 (v/v)) to givetert-butyl(2-isobutyl-6-{[(methylsulfonyl)amino]methyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.13 g, 84%) as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.15–2.35 (1H,m), 2.80 (3H, s), 4.07 (2H, d, J=7.2 Hz), 4.20 (2H, d, J=5.8 Hz), 4.29(2H, d, J=6.6 Hz), 4.52 (1H, br), 4.71 (1H, bt, J=5.8 Hz), 6.86 (1H, d,J=1.2 Hz), 7.20–7.30 (2H, m), 7.44 (1H, dd, J=1.6 8.0 Hz), 7.45–7.60(3H, m), 8.44 (1H, d, J=8.0 Hz).

(2)N-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]methyl}methanesulfoneamidehydrochloride (0.097 g, 100%) as a pale yellow powder. [synthesizedaccording to the method similar to that in Example 279 (3) fromtert-butyl(2-isobutyl-6-{[(methylsulfonyl)amino]methyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate(0.11 g, 0.21 mmol)]

¹H-NMR (DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.95–2.20 (1H, m), 2.80 (3H,s), 3.86 (2H, bs), 4.07 (2H, d, J=7.0 Hz), 4.14 (2H, d, J=6.2 Hz), 6.88(1H, s), 7.35–7.45 (2H, m), 7.50–7.65 (4H, m), 7.63 (1H, t, J=6.2 Hz),8.32 (1H, d, J=8.0 Hz), 8.55 (3H, bs). Melting point: 117–120° C.

Example 2893,6-Bis(aminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinonedihydrochloride

(1) To a solution of crudetert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate(0.16 g)(Example 286) in tetrahydrofuran (2 mL) was added di-t-butyldicarbonate (0.086 mL, 0.36 mmol), and the mixture was stirred at roomtemperature for 4 h. The reaction mixture was washed with water (4 mL)and concentrated. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=4:1 (v/v)) to givetert-butyl(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)methylcarbamate(0.14 g, 93%) as a colorless powder.

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.39 (9H, s), 1.42 (9H, s),2.15–2.35 (1H, m), 4.07 (2H, d, J=7.4 Hz), 4.19 (2H, d, J=6.6 Hz), 4.26(2H, d, J=6.6 Hz), 4.45 (1H, br), 4.81 (1H, br), 6.81 (1H, d, J=1.1 Hz),7.20–7.30 (2H, m), 7.30–7.40 (1H, m), 7.45–7.55 (3H, m), 8.42 (1H, d,J=8.0 Hz).

(2) 3,6-Bis(aminomethyl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinonedihydrochloride (0.080 g, 76%) as colorless powder. [synthesizedaccording to the method similar to that in Example 279 (3) fromtert-butyl(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)methylcarbamate(0.14 g, 0.26 mmol)]

¹H-NMR (DMSO-d₆) δ: 0.91 (6H, d, J=6.6 Hz), 1.95–2.20 (1H, m), 3.85 (2H,bs), 4.01 (2H, bs), 4.10 (2H, d, J=6.6 Hz), 7.02 (1H, d, J=1.0 Hz),7.35–7.45 (2H, m), 7.50–7.60 (3H, m), 7.72 (1H, dm, J=8.4 Hz), 8.36 (1H,d, J=8.4 Hz), 8.45 (3H, bs), 8.62 (3H, bs). Melting point: 282–285° C.

Example 2903-(Aminomethyl)-2-isobutyl-4-phenyl-6-[5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl]-1(2H)-isoquinolinonedihydrochloride

(1) A mixture of ethyl trifluoroacetate (0.038 mL, 0.31 mmol) andhydrazine monohydrate (0.026 mL, 0.50 mmol) in tetrahydrofuran (3 mL)was refluxed in a sealed tube for 1 h, the reaction was allowed to coolto room temperature. To the mixture were addedtert-butyl{6-[amino(imino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamatediacetate (0.14 g, 0.25 mmol) and sodium hydroxide (0.027 g, 0.55 mmol),and the resulting mixture was refluxed for 3 h. The reaction mixture waspartitioned between water (10 mL) and ethyl acetate (30 mL). The organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel-column chromatography (n-hexane:ethyl acetate=3:1(v/v)) to givetert-butyl{2-isobutyl-1-oxo-4-phenyl-6-[5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.074 g, 55%) as a colorless powder.

¹H-NMR (CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.43 (9H, s), 2.10–2.35 (1H,m), 4.08 (2H, d, J=7.4 Hz), 4.18 (2H, d, J=5.2 Hz), 4.71 (1H, br),7.20–7.30 (3H, m), 7.35–7.50 (4H, m), 8.02 (1H, dd, J=1.6, 8.6 Hz), 8.46(1H, d, J=8.6 Hz).

(2)3-(Aminomethyl)-2-isobutyl-4-phenyl-6-[5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl]-1(2H)-isoquinolinonedihydrochloride (0.063 g, 100%) as yellow crystals. [synthesizedaccording to the method similar to that in Example 279 (3) fromtert-butyl{2-isobutyl-1-oxo-4-phenyl-6-[5-(trifluoromethyl)-1H-1,2,4-triazol-2-yl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.065 g, 0.12 mmol)]

¹H-NMR (DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 1.72 (1H, br), 2.05–2.20(1H, m), 3.88 (2H, bs), 4.09 (2H, d, J=7.2 Hz), 7.40–7.50 (2H, m),7.55–7.70 (4H, m), 8.23 (1H, dd, J=1.6, 8.4 Hz), 8.50 (3H, bs), 8.52(1H, d, J=8.4 Hz). Melting point: 140–143° C.

Example 2913-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamidinedihydrochloride

This compound was synthesized according to the method similar to that inExample 279 (3) fromtert-butyl{6-[amino(imino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamatediacetate.

¹H-NMR (DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 2.00–2.20 (1H, m), 3.90 (2H,bs), 4.12 (2H, d, J=7.0 Hz), 7.24 (1H, d, J=1.6 Hz), 7.40–7.50 (2H, m),7.50–7.65 (3H, m), 7.86 (1H, dd, J=1.6, 8.4 Hz), 8.49 (1H, d, J=8.4 Hz),8.69 (3H, bs), 9.26 (2H, bs), 9.52 (2H, bs). Melting point: 171–173° C.

Example 292 Methyl2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1H-imidazole-4-carboxylatedihydrochloride

(1) To a mixture oftert-butyl{6-[amino(hydroxyimino)-methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.47 g, 1.0 mmol) and triethylamine (0.17 mL, 1.2 mmol) in ethylacetate (10 mL) was added methylpropionate (0.10 g, 1.2 mmol), and themixture was stirred at room temperature for 17 h. The reaction mixturewas poured into water (5 mL), and the organic layer was separated. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. To the residue was added p-xylene(10 mL), the mixture was refluxed for 40 h. The reaction mixture wasdiluted with ethyl acetate (100 mL), and the solution was washed withwater, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1 (v/v)) to give methyl2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1H-imidazole-4-carboxylate(0.22 g, 42%) as an orange powder.

¹H-NMR (CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.53 (9H, s), 2.00–2.25 (1H,m), 3.87 (3H, s), 4.00–4.25 (4H, m), 6.37 (1H, br), 7.15–7.25 (1H, m),7.25–7.55 (7H, m) 7.82 (1H, dm, J=8.4 Hz), 8.23 (1H, d, J=8.4 Hz).

(2) A solution of methyl2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1H-imidazole-4-carboxylate(0.10 g, 0.19 mmol) in trifluoroacetic acid (3 mL) was stirred at roomtemperature for 5 min. The reaction mixture was concentrated, andpurified by HPLC. The desired fractions were concentrated and then tothe residue was added a 4N hydrogen chloride, ethyl acetate solution (1mL). The mixture was concentrated, and the residue was recrystallizedfrom ethanol-ethyl acetate (10:1, v/v, 2 mL) to give methyl2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1H-imidazole-4-carboxylatedihydrochloride (0.050 g, 53%) as a yellow powder.

¹H-NMR (DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.00–2.25 (1H, m), 3.77 (3H,s), 3.84 (2H, s), 4.08 (2H, d, J=7.2 Hz), 7.40–7.50 (3H, m), 7.55–7.65(4H, m), 7.90 (1H, s), 8.20 (1H, dd, J=1.8, 8.4 Hz), 8.43 (1H, d, J=8.4Hz), 8.51 (3H, bs). Melting point: 266–270° C.

Example 293 Ethyl3-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,2,4-oxadiazole-5-carboxylatehydrochloride

(1) To a mixture oftert-butyl{6-[amino(hydroxyimino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate(0.23 g, 0.50 mmol) and pyridine (0.043 mL, 0.53 mmol) in toluene (20mL), was added ethyl chlorooxoacetate (0.059 mL, 0.53 mmol), and themixture was stirred at room temperature for 1 h and at 80° C. for 1 h.The reaction mixture was partitioned between water (50 mL) and ethylacetate (50 mL). The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=20:1–1:3 (v/v)) and recrystallized from diisopropyl ether-ethylacetate (20:1, v/v, 5 mL) to give ethyl3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1,2,4-oxadiazole-5-carboxylate(0.13 g, 48%) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.43 (9H, s), 1.47 (3H, t,J=7.2 Hz), 2.15–2.35 (1H, m), 4.11 (2H, d, J=7.2 Hz), 4.22 (2H, d, J=5.6Hz), 4.45–4.60 (1H, br), 4.54 (2H, q, J=7.2 Hz), 7.25–7.35 (2H, m),7.50–7.60 (3H, m), 7.74 (1H, d, J=1.2 Hz), 8.17 (1H, dd, J=1.2, 8.4 Hz),8.60 (1H, d, J=8.4 Hz).

(2) A solution of ethyl3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1,2,4-oxadiazole-5-carboxylate(0.070 g, 0.13 mmol) in trifluoroacetic acid (3 mL) was stirred at roomtemperature for 5 min. The reaction mixture was concentrated, and to theresidue was added a solution of 4N hydrogen chloride in ethyl acetate (3mL). The mixture was concentrated, and the residue was recrystallizedfrom diisopropyl ether-ethyl acetate-methanol (15:40:1, v/v, 5 mL) togive ethyl3-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,2,4-oxadiazole-5-carboxylatehydrochloride (0.061 g, 100%) as a colorless powder.

¹H-NMR (DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 1.34(3H, t, J=7.2 Hz),2.00–2.20 (1H, m), 3.90 (2H, bs), 4.10 (2H, d, J=5.0 Hz), 4.43 (2H, d,J=7.2 Hz), 7.40–7.50 (2H, m), 7.55–7.70 (4H, m), 8.22 (1H, dd, J=1.4,8.4 Hz), 8.30–8.60 (3H, br), 8.55 (1H, d, J=8.4 Hz). Melting point:266–270° C.

Reference Example 1 2-Benzoyl-4-bromobenzoic Acid

A mixture of benzene (2.94 ml), o-dichlorobenzene (20 ml) and aluminumchloride (5.87 g) was cooled to 5° C. and 5-bromophthalic anhydride (5.0g) was added by small portions while maintaining the temperature of themixture below 10° C. The mixture was stirred at around 25° C. for 1 hand then at 80° C. for 1 h. The reaction mixture was cooled to around 5°C. and ethyl acetate (40 ml) was added dropwise. Water (20 ml) was addeddropwise below 40° C. The organic layer was separated and 4Nhydrochloric acid (20 ml) was added. The mixture was stirred until theprecipitated solid was dissolved. The organic layer was separated andwashed with water (20 ml). The solvent was evaporated and toluene (30ml) and ethyl acetate (3 ml) were added to the residue, which wasfollowed by heating to 80° C. The obtained solution was cooled to 25° C.over 30 min and the precipitated crystals were collected by filtration.The crystals were dissolved in a mixture of toluene (30 ml) and ethylacetate (1.5 ml) by heating and the obtained solution was cooled to 25°C. and then to 5° C. The precipitated crystals were collected byfiltration and washed with toluene, to give the title compound (2.81 g,yield 41.8%).

¹H-NMR(300 MHz, CDCl₃) δ: 7.41–7.46(2H, m), 7.51–7.60(2H, m),7.69–7.72(3H, m), 7.94(1H, d, J=8.4 Hz)

Reference Example 2 Isobutylaminoacetonitrile

To a mixture of isobutylamine (180.3 g), triethylamine (274.9 g) andethyl acetate (900 ml) was added dropwise bromoacetonitrile (304.8 g)under ice-cooling below 30° C. over about 2 h. The reaction mixture wasadjusted to 25° C. stirred for 3 h and washed with water (900 ml) and10% brine (900 ml). The solvent was evaporated and the obtainedpale-yellow oil was distilled under reduced pressure. The bP_(10mmHg)82° C. fractions were collected to give the title compound (198.3 g).

¹H-NMR(CDCl₃), δ: 0.94(6H, d, J=6.6 Hz), 1.17(1H, br), 1.74(1H, m),2.54(2H, d, J=6.6 Hz), 3.59(2H, s)

Experimental Example 1

1) Preparation of Dipeptidyl Peptidase IV Crude Enzyme Solution

The enzyme activity of dipeptidyl peptidase IV present in human colonicadenocarcinoma-derived cell line Caco-2 cell membrane has been alreadyreported by Yong S. Chung et al. (Cancer Research, vol. 45, pp.2976–2982, 1985).

A dipeptidyl peptidase IV crude enzyme solution was prepared fromculture cell of Caco-2 (ATCC HTB-37). The Caco-2 cells were cultured inD-MEM medium (manufactured by Nissui Pharmaceutical Co., Ltd.)containing 10% FBS (fetal calf serum (manufactured by GIBCO)). The cellextract was prepared by soaking the cells collected by removing themedium in 20 mM phosphate buffer. (pH 7.5) containing 0.5% Triton X-100,extracting for 30 min in an ice bath and separating the supernatantobtained by centrifugation 1500 g for 30 min. The cell extract (22 ml)was applied to a column of Sephadex G-200 (600 ml, manufactured byPharmacia Corporation) equilibrated with 20 mM Tris-hydrochloride buffer(pH 7.5) and eluted with the same buffer. The elution was fractionatedby 10 ml, examined for enzyme activity and 190 ml–280 ml fractions (90ml) were collected. The same buffer (260 ml) was added for dilution togive a crude enzyme solution (14 mU/ml, 350 ml). One unit of thedipeptidyl peptidase IV enzyme activity was defined as an enzyme amountthat produces 1 μmol of p-nitroaniline from glycylprolyl-p-nitroanilidein 1 min.

2) Determination of Caco-2-Derived Dipeptidyl Peptidase IV InhibitoryActivity

The reaction was carried out according to the method of Nagatsu et al.(Analytical Biochemistry, vol. 74, pp. 466–467, 1976) using a 96 wellflat-bottomed plate at 37° C.

An N,N-dimethylformamide solution (5 μl) containing the test compoundwas added to a mixture of water (25 μl), 1M Tris-hydrochloride buffer(10 μl, pH 7.5) and 1 mM aqueous glycylprolyl-p-nitroanilide(Gly-Pro-p-NA; manufactured by Backem AG) solution (50 μl) to prepare amixed solution. The Caco-2-derived dipeptidyl peptidase IV crude enzymesolution (10 μl) obtained in the aforementioned 1) was added to theabove-mentioned mixed solution and the enzyme reaction was started at37° C. The absorbance after 0 h and 3 h was measured using a microplatereader (Multiskan Bichromatic; manufactured by Labsystems) at awavelength of 405 nm and an increase (ΔODs) was determined. At the sametime, an increase (ΔODc) in absorbance of the reaction mixture withoutthe test compound, and an increase (ΔODb) in absorbance of the reactionmixture without the test compound and the enzyme were determined andpercent inhibition of dipeptidyl peptidase IV enzyme activity wascalculated from the following formula:{1-[(ΔODs−ΔODb)/(ΔODc−ΔODb)]}×100

The dipeptidyl peptidase IV inhibitory activity of the test compoundgroup is expressed in IC₅₀ value (μM) and shown in Table 8.

TABLE 8 Test compound IC₅₀ value (Example No.) (μM) 95 0.28 109 0.36 1120.25

As shown above, the compound of the present invention has a superiordipeptidyl peptidase IV enzyme activity, and is useful as an agent forthe prophylaxis or treatment of diabetes and the like.

Experimental Example 2

Determination of Dipeptidyl Peptidase IV Inhibitory Activity in RatPlasma

The reaction was carried out according to the method of Raymond et al.(Diabetes, vol. 47, pp. 1253–1258, 1998) using a 96 well flat-bottomedplate at 30° C. An N,N-dimethylformamide solution (1 μl) containing thetest compound was added to a mixture of water (69 μl), 1MTris-hydrochloride buffer (10 μl, pH 7.5) and 1 mM aqueous Gly-Pro-p-NAsolution (100 μl) to prepare a mixed solution. Plasma (20 μl) preparedfrom blood of SD rat by a conventional method was added theabove-mentioned, mixed solution and the enzyme reaction was started at30° C. The absorbance after 0 h and 1 h was measured using a microplatereader at a wavelength of 405 nm and an increase (ΔODs) was determined.At the same time, an increase (ΔODc) in absorbance of the reactionmixture without the test compound, and an increase (ΔODb) in absorbanceof the reaction mixture without the test compound and the enzyme weredetermined and percent inhibition of dipeptidyl peptidase IV enzymeactivity was calculated from the following formula:{1-[(ΔODs−ΔODb)/(ΔODc−ΔODb)]}×100

The dipeptidyl peptidase IV inhibitory activity of the test compoundgroup is expressed in IC₅₀ value (μM) and shown in Table 9.

TABLE 9 Test compound IC₅₀ value (Example No.) (μM) 95 0.18 109 0.15 1120.32

As shown above, the compound of the present invention has a superiordipeptidyl peptidase IV enzyme activity, and is useful as an agent forthe prophylaxis or treatment of diabetes and the like.

Experimental Example 3

Plasma Glucose-lowering Effect and Insulinotropic Effect in Rat

Female Wistar fatty rats (17-week-old, 6 per group) were fastedovernight and blood was drawn from the tail vein. The plasma glucoselevel before administration of the test compound was measured. Then thetest compound (3 mg/kg body weight/5 mL) suspended in 0.5% methylcellulose was orally administered to the rats using a gastric tube. Oralglucose tolerance test (1 g/kg body weight/5 mL) was started 60 minlater. Blood was drawn at 30 min after starting glucose load, and plasmaglucose level and insulin level of the serum were measured. The plasmaglucose level was measured using an automatic analyzer (HITACHI 7070)and the insulin level was measured using a radio immunoassay kit(trademark: SHIONORIA insulin kit (manufactured by Shionogi & Co.,Ltd.)).

The plasma glucose level and insulin level of the test compound groupare expressed in a value (%) relative to the control group and shown inTable 10.

TABLE 10 Test compound Plasma glucose level insulin level (Example No.)(% of control) (% of control) 95 82 188 109 73 205 112 76 255

As shown above, the compound of the present invention has a superiorplasma glucose level-lowering effect and a superior insulinotropiceffect, and is useful as an agent for the prophylaxis or treatment ofdiabetes and the like.

Formulation Example 1 (production of capsule) 1) compound of Example 9530 mg 2) fine cellulose powder 10 mg 3) lactose 19 mg 4) magnesiumstearate 1 mg total 60 mg 1), 2), 3) and 4) are mixed and filled ingelatin capsules. Formulation Example 2 (production of tablet) 1)compound of Example 95 30 g 2) lactose 50 g 3) corn starch 15 g 4)calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g total of1000 tablets 140 g

The entire amounts of 1), 2) and 3), and 30 g of 4) are kneaded withwater, dried in vacuo and granulated. The granules are mixed with 14 gof 4) and 1 g of 5) and the mixture is compressed with a tabletingmachine, whereby 1000 tablets containing 30 mg of compound of Example 95per tablet are obtained.

The compound and the pharmaceutical agent of the present invention showa superior peptidase (preferably dipeptidyl peptidase-IV)-inhibitoryactivity and are useful as an agent for the prophylaxis or treatment ofdiabetes and the like.

This application is based on patent application Nos. 2001-27349,2001-292388 and 2001-382232 filed in Japan, the contents of which arehereby incorporated by reference. All of the references cited herein,including patents, patent applications and publications, are herebyincorporated in their, entireties by reference.

1. A compound of the formula

wherein ring A is a 5 to 10-membered aromatic ring having 1 to 3substituent(s) selected from 1) a nitro group; 2) a cyano group; 3) aC₁₋₃alkylenedioxy group; 4) a C₁₋₁₀alkyl group or a C₂₋₁₀ alkenyl group,each having 1 to 3 substituent(s) selected from hydroxy group, carboxylgroup, alkoxycarbonyl group having 2 to 8 carbon atoms, carbamoyl group,cyano group, amino group, alkanoylamino group having 2 to 8 carbonatoms, alkoxycarbonylamino group having 2 to 8 carbon atoms andalkylsulfonylamino group having 1 to 8 carbon atom(s); 5) an alkoxygroup having 1 to 10 carbon atom(s), a cycloalkyloxy group having 3 to10 carbon atoms or an aralkyloxy group having 7 to 13 carbon atoms, eachhaving 1 to 3 substituent(s) selected from alkoxy group having 1 to 3carbon atom(s), alkoxycarbonyl group having 2 to 5 carbon atoms,alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group,hydroxy group, carboxyl group, amino group, alkanoylamino group having 2to 5 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms; 6)an acyl group; 7) an optionally substituted amino group; 8) an arylgroup having 6 to 14 carbon atoms; 9) an optionally substituted thiolgroup; 10) an optionally substituted heterocyclic group; and 11) anamidino group; R¹ and R² are the same or different and each is anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; X is a bond, —O—, —S—, —SO—, —SO₂— or —NR³— (R³ is ahydrogen atom or an optionally substituted hydrocarbon group); and L isa divalent hydrocarbon group or a salt thereof.
 2. The compound of claim1, wherein the 5 to 10-membered aromatic ring for ring A is a benzenering.
 3. The compound of claim 1, wherein R¹ is an alkyl group having 1to 10 carbon atom(s).
 4. The compound of claim 1, wherein R¹ is an alkylgroup having 4 to 10 carbon atoms.
 5. The compound of claim 1, wherein Xis a bond or —O—.
 6. The compound of claim 1, wherein the divalenthydrocarbon group for L is an alkylene group having 1 to 10 carbonatom(s).
 7. The compound of claim 1, wherein R² is an optionallysubstituted hydrocarbon group.
 8. The compound of claim 1, wherein R² isan alkyl group having 1 to 10 carbon atom(s), an aryl group having 6 to14 carbon atoms or an aralkyl group having 7 to 13 carbon atoms, eachoptionally having 1 to 3 substituent(s) selected from halogen atom,hydroxy group, nitro group, amino group, optionally halogenated alkylgroup having 1 to 6 carbon atom(s), alkoxy group having 1 to 6 carbonatom(s), aromatic heterocyclic group and cycloalkyl group having 3 to 10carbon atoms.
 9. The compound of claim 1, which is2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carbonitrile,2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxylicacid,2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxamide,ethyl2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxylate,(E)-3-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenamide,(E)-3-[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenamide,3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide,2-[[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy]acetamide,or a salt thereof.
 10. A crystal of2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carbonitrileor a salt thereof.
 11. A crystal of2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxamideor a salt thereof.
 12. A crystal of2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxamideor a salt thereof.
 13. A crystal of ethyl2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazole-4-carboxylateor a salt thereof.
 14. A crystal of(E)-3-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenamideor a salt thereof.
 15. A crystal of(E)-3-[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]-2-propenamideor a salt thereof.
 16. A crystal of3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamideor a salt thereof.
 17. A crystal of2-[[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy]acetamideor a salt thereof.
 18. A pharmaceutical composition comprising acompound of the formula

wherein ring A is a 5 to 10-membered aromatic ring having 1 to 3substituent(s) selected from 1) a nitro group; 2) a cyano group; 3) aC₁₋₃ alkylenedioxy group; 4) a C₁₋₁₀ alkyl group or a C₂₋₁₀ alkenylgroup, each having 1 to 3 substituent(s) selected from hydroxy group,carboxyl group, alkoxycarbonyl group having 2 to 8 carbon atoms,carbamoyl group, cyano group, amino group, alkanoylamino group having 2to 8 carbon atoms, alkoxycarbonylamino group having 2 to 8 carbon atomsand alkylsulfonylamino group having 1 to 8 carbon atom(s); 5) an alkoxygroup having 1 to 10 carbon atom(s), a cycloalkyloxy group having 3 to10 carbon atoms or an aralkyloxy group having 7 to 13 carbon atoms, eachhaving 1 to 3 substituent(s) selected from alkoxy group having 1 to 3carbon atom(s), alkoxycarbonyl group having 2 to 5 carbon atoms,alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group,hydroxy group, carboxyl group, amino group, alkanoylamino group having 2to 5 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms; 6)an acyl group; 7) an optionally substituted amino group; 8) an arylgroup having 6 to 14 carbon atoms; 9) an optionally substituted thiolgroup; 10) an optionally substituted heterocyclic group; and 11) anamidino group; R¹ and R² are the same or different and each is anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; X is a bond, —O—, —S—, —SO—, —SO₂— or —NR³— (R³ is ahydrogen atom or an optionally substituted hydrocarbon group); and L isa divalent hydrocarbon group or a salt thereof and a pharmacologicallyacceptable carrier.
 19. A pharmaceutical composition comprising thepharmaceutical composition of claim 19 and a pharmacologicallyacceptable carrier in combination with at least one member selected froman insulin preparation, an insulin sensitizer, an α-glucosidaseinhibitor, a biguanide and an insulin secretagogue.
 20. A method oftreatment of diabetes in a mammal, which method comprising administeringa compound of the formula

wherein ring A is a 5 to 10-membered aromatic ring having 1 to 3substituent(s) selected from 1) a nitro group; 2) a cyano group; 3) aC₁₋₃ alkylenedioxy group; 4) a C₁₋₁₀ alkyl group or a C₂₋₁₀ alkenylgroup, each having 1 to 3 substituent(s) selected from hydroxy group,carboxyl group, alkoxycarbonyl group having 2 to 8 carbon atoms,carbamoyl group, cyano group, amino group, alkanoylamino group having 2to 8 carbon atoms, alkoxycarbonylamino group having 2 to 8 carbon atomsand alkylsulfonylamino group having 1 to 8 carbon atom(s); 5) an alkoxygroup having 1 to 10 carbon atom(s), a cycloalkyloxy group having 3 to10 carbon atoms or an aralkyloxy group having 7 to 13 carbon atoms, eachhaving 1 to 3 substituent(s) selected from alkoxy group having 1 to 3carbon atom(s), alkoxycarbonyl group having 2 to 5 carbon atoms,alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group,hydroxy group, carboxyl group, amino group, alkanoylamino group having 2to 5 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms; 6)an acyl group; 7) an optionally substituted amino group; 8) an arylgroup having 6 to 14 carbon atoms; 9) an optionally substituted thiolgroup; 10) an optionally substituted heterocyclic group; and 11) anamidino group; R¹ and R² are the same or different and each is anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; X is a bond, —O—, —S—, —SO—, —SO₂— or —NR³— (R³ is ahydrogen atom or an optionally substituted hydrocarbon group); and L isa divalent hydrocarbon group, a salt thereof or a prodrug thereof to themammal.
 21. A method of treatment of diabetic complications in a mammal,which method comprising administering a compound of the formula

wherein ring A is a 5 to 10-membered aromatic ring having 1 to 3substituent(s) selected from 1) a nitro group; 2) a cyano group; 3) aC₁₋₃ alkylenedioxy group; 4) a C₁₋₁₀ alkyl group or a C₂₋₁₀ alkenylgroup, each having 1 to 3 substituent(s) selected from hydroxy group,carboxyl group, alkoxycarbonyl group having 2 to 8 carbon atoms,carbamoyl group, cyano group, amino group, alkanoylamino group having 2to 8 carbon atoms, alkoxycarbonylamino group having 2 to 8 carbon atomsand alkylsulfonylamino group having 1 to 8 carbon atom(s); 5) an alkoxygroup having 1 to 10 carbon atom(s), a cycloalkyloxy group having 3 to10 carbon atoms or an aralkyloxy group having 7 to 13 carbon atoms, eachhaving 1 to 3 substituent(s) selected from alkoxy group having 1 to 3carbon atom(s), alkoxycarbonyl group having 2 to 5 carbon atoms,alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group,hydroxy group, carboxyl group, amino group, alkanoylamino group having 2to 5 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms; 6)an acyl group; 7) an optionally substituted amino group; 8) an arylgroup having 6 to 14 carbon atoms; 9) an optionally substituted thiolgroup; 10) an optionally substituted heterocyclic group; and 11) anamidino group; R¹ and R² are the same or different and each is anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; X is a bond, —O—, —S—, —SO—, —SO₂— or —NR³— (R³ is ahydrogen atom or an optionally substituted hydrocarbon group); and L isa divalent hydrocarbon group, a salt thereof or a prodrug thereof to themammal.